Flap modulators

ABSTRACT

The present invention relates to compounds of Formula (I), or a form thereof, wherein ring A, R 1 , L and R 2  are as defined herein, useful as FLAP modulators. The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 14/765,552 filed onAug. 3, 2015, which is a 371 national phase of International ApplicationNo. PCT/US2014/014088 filed on Jan. 31, 2014, which claims the benefitof U.S. Provisional Application No. 61/760,615 filed on Feb. 4, 2013 andU.S. Provisional Application No. 61/798,951 filed on Mar. 15, 2013, allof which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to substituted compounds useful as5-lipoxygenase-activating protein (FLAP) modulators, pharmaceuticalcompositions of such compounds, methods of preparation and use thereof.More particularly, FLAP modulators are useful for preventing, treatingor ameliorating FLAP-mediated diseases and/or disorders, including thoseinflammation diseases and/or disorders associated with dermatologicaland respiratory disorders, allergic disorders, autoimmunity, cancer,cardiovascular and metabolic disorders.

BACKGROUND OF THE INVENTION

FLAP is a key initiator of the leukotriene synthesis pathway that bindsand then transfers arachidonic acid to 5-lipoxygenase (M. Abramovitz etal., “5-lipoxygenase-activating protein stimulates the utilization ofarachidonic acid by 5-lipoxygenase,” Eur. J. Biochem., 1993, 215,105-11). FLAP has been demonstrated to interact with LTC₄ synthase, andcould putatively modulate the production of LTC₄ (T. Strid et al.,“Distinct parts of leukotriene C(4) synthase interact with5-lipoxygenase and 5-lipoxygenase activating protein,” Biochem. Biophys.Res. Comm., 2009, 381(4), 518-22). Modulation (including withoutlimitation inhibition) or genetic deletion of FLAP blocks leukotrieneproduction, specifically LTB₄, the cysteinyl leukotrienes (LTC₄, LTD₄and LTE₄) as well as 5-oxo-ETE (J. Z. Haeggström et al., “Lipoxygenaseand leukotriene pathways: biochemistry, biology, and roles in disease,”Chem Rev., 2011, 111(10), 5866-98).

Leukotrienes are immune-modulating lipids formed from arachidonic acid(reviewed in B. Samuelsson, “Leukotrienes: mediators of immediatehypersensitivity reactions and inflammation,” Science, 1983, 220,568-75). They are synthesized primarily by eosinophils, neutrophils,mast cells, basophils, dendritic cells, macrophages and monocytes.Leukotrienes mediate multiple biological effects including, by way ofexample only, smooth muscle contraction, leukocyte recruitment andactivation, cytokine secretion, fibrosis, mucous secretion, and vascularfunction (J. Z. Haeggström, at 5866-98).

FLAP-deficient mice are healthy and reproduce normally. They do notproduce leukotrienes and have decreased susceptibility in mouse modelsof arthritis (R. J. Griffiths et al., “Collagen-induced arthritis isreduced in 5-lipoxygenase-activating protein-deficient mice,” J. Exp.Med., 1997, 185, 1123-29). In humans, FLAP itself has been linked bygenetic studies to respiratory disorders and cardiovascular disease,including myocardial infarction, atherosderosis, cerebral infarctions,coronary artery disease and stroke (A. Helgadottir et al., “The geneencoding 5-lipoxygenase activating protein confers risk of myocardialinfarction, atherosclerosis and stroke,” Nat. Genet., 2004, 36, 233-39;A. S. Tulah et al., “The role of ALOX5AP, LTA4H and LTB4R polymorphismsin determining baseline lung function and COPD susceptibility in UKsmokers,” BMC Med. Genet., 2011, 29(12), 173; R. Ji et al., “Geneticvariants in the promoter region of the ALOX5AP gene and susceptibilityof ischemic stroke,” Cerebrovasc. Dis., 2011, 32(3), 261-68; J. W.Holloway et al., “The role of LTA4H and ALOX5AP polymorphism in asthmaand allergy susceptibility,” Allergy, 2008, 63(8), 1046-53; J. Nair etal., “Expression analysis of leukotriene-inflammatory gene interactionnetwork in patients with coronary artery disease,” J Atheroscler.Thromb., 2013; L. F. Chi et al., “Interaction between ALOX5AP and CYP3A5gene variants significantly increases the risk for cerebral infarctionsin Chinese,” Neuroreport., 2013). In addition, studies using animalmodels support a causative role for leukotrienes in aortic aneurisms,atherosclerosis, pulmonary arterial hypertension, myocardial infarction,atherosclerosis, and stroke (reviewed in J. Z. Haeggström, at 5866-98).

Leukotrienes also play a role in autoimmune disorders such as rheumatoidarthritis, inflammatory bowel disease, nephritis, spondyloarthritis,polymyositis, dermatomyositis, gouty effusions, systemic lupuserythematosus, systemic sclerosis, Alzheimer's disease and multiplesclerosis (S. Chwieśko-Minarowska et al., “The role of leukotrienes inthe pathogenesis of systemic sclerosis,” Folia Histochem. Cytobiol.,2012, 50(2), 180-85; M. Rosnowska et al., “Leukotrienes C4 and B4 incerebrospinal fluid of patients with multiple sclerosis,” Pol.Merkuriusz Lek., 1997, 2, 254-55; and reviewed in J. Z. Haeggström, at5866-98; I. Loell et al., “Activated LTB4 pathway in muscle tissue ofpatients with polymyositis or dermatomyositis,” Ann. Rheum. Dis., 2013,72(2), 293-99; J. Chu et al., “Involvement of 5-lipoxygenase activatingprotein in the amyloidotic phenotype of an Alzheimer's disease mousemodel,” J. Neuroinflammation, 2012, 9, 127). Leukotrienes have also beenimplicated in several aspects of carcinogenesis including tumor cellproliferation, differentiation, and apoptosis, tumor-associatedangiogenesis, as well as the migration and invasion of carcinoma cells(D. Wang and R. N. Dubois, “Eicosanoids and cancer,” Nat. Rev. Cancer,2010, 10(3), 181-93).

Leukotrienes play a key role in allergic disorders such as allergicrhinitis, allergic dermatitis and asthma, as well as respiratorydisorders such as exacerbations, non-allergic asthma, aspirinexacerbated respiratory disease, fibrotic lung diseases, acuterespiratory distress syndrome and chronic obstructive pulmonary disease(reviewed in J. Z. Haeggström at 5866-98). Approved antagonists of theLTC₄ receptor and leukotriene synthesis modulators such as zileuton haveshown clinical efficacy in a variety of respiratory disorders (reviewedin M. E. Krawiec and S. E. Wenzel, “Leukotriene modulators andnon-steroidal therapies in the treatment of asthma,” Expert. Opin.Pharmacotherapy, 2001, 2(1), 47-65).

All the above evidence supports a key role of leukotrienes in a varietyof human diseases and/or disorders, and FLAP modulation would beeffective for the prevention, treatment, or amelioration of theseimmune-mediated inflammatory diseases and/or disorders. Furthermore,there still remains a need for FLAP modulator compounds that havepharmacokinetic and pharmacodynamic properties suitable for use as humanpharmaceuticals.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides novel compoundsuseful as, for example, FLAP modulators (including without limitationnovel compounds that inhibit FLAP), methods of preparing such compounds,pharmaceutical compositions comprising one or more such compounds,methods of preparing pharmaceutical compositions comprising one or moresuch compounds, and methods of prophylaxis, treatment, amelioration,including without limitation inhibition, of one or more diseases and/ordisorders associated with FLAP using such compounds or pharmaceuticalcompositions.

One aspect of the present invention is directed to compounds, methods,and compositions for the treatment or prophylaxis or amelioration of avariety of diseases and/or disorders that are mediated or sustainedthrough the activity of leukotrienes, including pulmonary, allergic,fibrotic, neurological, inflammatory, autoimmune and cardiovasculardiseases and cancer or associated symptoms or complications thereof.More specifically, this invention is directed to a method of treatingexacerbations, non-allergic asthma, fibrotic lung diseases, acuterespiratory distress syndrome and chronic obstructive pulmonary disease,or associated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder, wherein the method comprisesadministering a FLAP modulator.

Another aspect of the present invention is directed to compounds,methods, and compositions for the treatment or prophylaxis oramelioration of cardiac and cardiovascular diseases and/or disorders, orassociated symptoms or complications thereof, that include but are notlimited to myocardial infarction, atherosclerosis, stroke andatherosclerosis aortic aneurisms, or associated symptoms orcomplications thereof, in a subject afflicted with such a disease and/ordisorder, wherein the method comprises administering a FLAP modulator.

Yet another aspect of the present invention is directed to compounds,methods, and compositions for the prophylaxis, treatment, oramelioration of autoimmune diseases and/or disorders, or associatedsymptoms or complications thereof, that include but are not limited torheumatoid arthritis, inflammatory bowel disease, nephritis,spondyloarthritis, polymyositis, dermatomyositis, gouty effusions,systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease,multiple sclerosis or allergic disorders that include but are notlimited to allergic rhinitis, allergic dermatitis and asthma, orassociated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder, wherein the method comprisesadministering a FLAP modulator.

Finally, one aspect of the present invention is directed to compounds,methods, and compositions for the prophylaxis, treatment, oramelioration of carcinogenesis including but not limited to tumor cellproliferation, differentiation, apoptosis, tumor-associatedangiogenesis, as well as the migration and invasion of carcinoma cells,or associated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder, wherein the method comprisesadministering a FLAP modulator.

Another aspect of the present invention features a compound of Formula(I)

wherein

L is a bond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂NH—, —CH₂C(═O)NH—,—CH₂C(OH)(H)CH₂—, or —CH₂C(OH)(H)CH₂NH—;

R₁ is halo, C₁₋₅-alkyl, C₃₋₆cycloalkyl, or cyclohexylmethyl;

R₂ is H, C₁₋₄alkyl, hydroxyl, amino, cyano, —CH₂C(═O)O-(tert-butyl),—CH₂C(═O)O-(ethyl), —CH₂C(═O)OH, —NHS(═O)₂CH₃,tert-butyl(dimethyl)silyl-oxy, —NHCH₃, —N(CH₃)₂, —NH-(Isopropyl),optionally substituted phenyl, optionally substituted 5-membered or6-membered heteroaryl, C₃₋₆cycloalkyl, or optionally substitutedheterocyclyl;

wherein the 5-membered or 6-membered heteroaryl, the heterocyclyl, orthe phenyl is optionally and independently substituted with 1-4substituents selected from the group consisting of:

C₁₋₄alkyl, —CH₂-methoxy, —C(═O)OH, —CH₂C(═O)OH, —C(═O)—O—CH₂CH₃,—C(═O)—O—CH₃, —C(═O)—O-(tert-butyl), —NH₂, —NHCH₃, —N(CH₃)₂,—NH-(isobutyl), —NH(CH₂)₂NHC(═O)—O-tert-butyl, —NH(CH₂)₂NH₂,—NH(CH₂)₂N(CH₃)₂, —C(═O)NH₂, —C(═O)CH₃, Oxo, halo, hydroxyl, methoxy,trifluoromethyl, trifluoromethoxy, methoxymethyl, —S(═O)₂CH₃,—S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂, —S—CH₃, cyano,1H-tetrazol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl,4′-(trifluoromethyl) phenyl, benzyl,1,5-dioxa-9-azaspiro[5.5]undecan-9-yl, 5-pyrimidine-2-amine, andpentafluoro-lambda˜6˜-sulfanyl;

ring A is selected from the group consisting of:

R₃ is H, cyano, methyl, methoxy, halo, or —NH₂;

R₄ is H, or methyl; and

R₅ is H, cyano, halo, CF₃, or —NH₂;

or an optical isomer, hydrate, metabolite, enantiomer, diastereomer,cis-trans isomer, racemate, prodrug or pharmaceutically acceptable saltthereof.

Another aspect of the present invention features a pharmaceuticalcomposition comprising at least one compound of Formula (I) and at leastone pharmaceutically acceptable carrier. The invention is also directedtowards providing a process for formulating a pharmaceuticalcomposition, comprising formulating a pharmaceutical composition of atleast one compound of Formula (I) and at least one pharmaceuticallyacceptable carrier. The present invention further relates to a processfor making a pharmaceutical composition comprising mixing any of thecompounds according to Formula (I) and a pharmaceutically acceptablecarrier.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease and/or disorder mediated byFLAP activity, comprising administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I). Such a diseaseand/or disorder can include, but is not limited to respiratorydisorders, cardiac and cardiovascular diseases, autoimmune disorders,carcinogenesis or associated symptoms or complications. Morespecifically, this invention is directed to a method of treatingexacerbations, non-allergic asthma, fibrotic lung diseases, acuterespiratory distress syndrome, chronic obstructive pulmonary diseasemyocardial infarction, atherosclerosis and stroke aortic aneurisms,atherosclerosis, rheumatoid arthritis, inflammatory bowel disease,nephritis, spondyloarthritis, polymyositis, dermatomyositis, goutyeffusions, systemic lupus erythematosus, systemic sclerosis, Alzheimer'sdisease, multiple sclerosis, allergic rhinitis, allergic dermatitis andasthma, tumor cell proliferation, differentiation, and apoptosis,tumor-associated angiogenesis, as well as the migration and invasion ofcarcinoma cells, or associated symptoms or complications thereof, in asubject afflicted with such a disease and/or disorder, or associatedsymptoms or complications thereof, wherein the method comprisesadministering a FLAP modulator to a subject in need thereof, atherapeutically effective amount of at least one compound of Formula(I), preferably in a pharmaceutical composition comprising at least onecompound of Formula (I).

Additional embodiments and advantages of the invention will becomeapparent from the detailed discussion, schemes, examples, and claimsbelow.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to novel FLAP modulators and compositions thereoffor the prophylaxis, treatment, or amelioration of numerous diseasesand/or disorders, including but not limited to respiratory diseasesand/or disorders, cardiac and cardiovascular diseases and/or disorders,autoimmune diseases and/or disorders, carcinogenesis, and associatedsymptoms or complications thereof.

One aspect of the present invention features a compound of Formula (I)

wherein

L is a bond, —CH₂—, —CH₂CH₂—, —CH₂C(OH)(H)CH₂, —CH₂CH₂CH₂—, —CH₂CH₂NH—,—CH₂C(═O)NH—, or —CH₂C(OH)(H)CH₂NH—;

R₁ is halo, C₁₋₅alkyl, C₃₋₆cycloalkyl, or cyclohexylmethyl;

R₂ is H, C₁₋₄alkyl, hydroxyl, amino, cyano, —CH₂C(═O)O-(tert-butyl),—CH₂C(═O)O-(ethyl),

-   —CH₂C(═O)OH, —NHS(═O)₂CH₃, tert-butyl(dimethyl)silyl-oxy, —NHCH₃,    —N(CH₃)₂, —NH-(Isopropyl), optionally substituted phenyl, optionally    substituted 5-membered or 6-membered heteroaryl, C₃₋₆cycloalkyl, or    optionally substituted heterocyclyl;

wherein the 5-membered or 6-membered heteroaryl, the heterocyclyl, orthe phenyl is optionally and independently substituted with 1-4substituents selected from the group consisting of:

C₁₋₄alkyl, —CH₂-methoxy, —C(═O)OH, —CH₂C(═O)OH, —C(═O)—O—CH₂CH₃,—C(═O)—O—CH₃, —C(═O)—O-(tert-butyl), —NH₂, —NHCH₃, —N(CH₃)₂,—NH-(isobutyl), —NH(CH₂)₂NHC(═O)—O-tert-butyl, —NH(CH₂)₂NH₂,—NH(CH₂)₂N(CH₃)₂, —C(═O)NH₂, —C(═O)CH₃, oxo, halo, hydroxyl, methoxy,trifluoromethyl, trifluoromethoxy, methoxymethyl, —S(═O)₂CH₃,—S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂, —S—CH₃, cyano,1H-tetrazol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl,4′-(trifluoromethyl) phenyl, benzyl,1,5-dioxa-9-azaspiro[5.5]undecan-9-yl, 5-pyrimidine-2-amine, andpentafluoro-lambda˜6˜-sulfanyl;

ring A is selected from the group consisting of:

R₃ is H, cyano, methyl, methoxy, halo, or —NH₂;

R₄ is H, or methyl; and

R₅ is H, cyano, halo, CF₃, or —NH₂.

Some embodiments of the present invention are given by compounds ofFormula (I), wherein R₁ is tert-butyl, cyclopropyl, cyclobutyl, orcyclopentyl, R₃ is H or cyano, R₄ is H, and R₅ is H.

Other embodiments are given by compounds of Formula (I), wherein R₁ istert-butyl, cyclobutyl, or cyclopentyl.

Yet, other embodiments are given by compounds of Formula (I), wherein R₁is tert-butyl or cyclobutyl, R₃ is H or cyano, R₄ is H, and R₅ is H.

Some embodiments are given by compounds of Formula (I), wherein ring Ais

In some of these embodiments, wherein ring A is

R₃ is cyano, and R₄ is cyano.

In some of these embodiments, wherein ring A is

R₃ is H, and R₄ is H.

Some embodiments are given by compounds of Formula (I), wherein R₁ istert-butyl.

Some embodiments are given by compounds of Formula (I), wherein R₁ iscyclobutyl.

In some of these embodiments, wherein R₁ is cyclobutyl, R₂ is—CH₂C(═O)O-(tert-butyl), —CH₂C(═O)O-(ethyl), —CH₂C(═O)OH, or—NHS(═O)₂CH₃.

In some of these embodiments, wherein R₁ is cyclobutyl, R₂ is optionallysubstituted phenyl, or optionally substituted 5-membered or 6-memberedheteroaryl.

In some of these embodiments, wherein R₁ is cyclobutyl, L is a bond or—CH₂—.

In some of these embodiments, wherein R₁ is cyclobutyl, ring A is

In some of these embodiments, wherein R₁ is cyclobutyl, ring A is

In some of these embodiments, wherein R₁ is cyclobutyl, ring A is

Some embodiments are given by compounds of Formula (I), wherein L is abond or —CH₂—.

In some of these embodiments, wherein L is a bond or —CH₂—, R₁ iscyclobutyl, and ring A is

In another embodiment, the present invention includes a compound ofFormula (I) wherein:

-   -   L is a bond or —CH₂—;    -   R₁ is tert-butyl or cyclobutyl;    -   R₂ is optionally substituted phenyl or an optionally substituted        6-membered heteroaryl;    -   wherein the substitution of the phenyl or the 6-membered        heteroaryl is selected from a group consisting of:    -   hydroxyl, fluoro, methoxy, cyano, amino, —C(═O)—NH₂, and        pentafluoro-lambda˜6˜-sulfanyl;    -   ring A is

and

-   -   R₃ is H or cyano.

In yet another embodiment, the present invention includes a compound ofFormula (I) wherein:

-   -   L is a bond or —CH₂—;    -   R₁ is tert-butyl or cyclobutyl;    -   R₂ is optionally substituted phenyl, optionally substituted        pyridine or optionally substituted pyrimidine;    -   wherein the substitution of the phenyl, the pyridine or the        pyrimidine is selected from a group consisting of:    -   hydroxyl, fluoro, methoxy, cyano, amino, —C(═O)—NH₂, and        pentafluoro-lambda˜6˜-sulfanyl; and    -   ring A is

The embodiments of the present invention also include the opticalisomers, hydrates, metabolites, enantiomers, diastereomers, cis-transisomers, racemates, prodrugs or pharmaceutically acceptable saltsthereof.

It is an embodiment of the present invention to provide a compoundselected from the compounds listed in Table 1.

TABLE 1 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine,3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol,3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol,5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoicacid,4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoicacid,5-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine,5-(3-{[4-Chloro-2-(methylsulfonyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine1-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-methyl}phenyl)-ethanone,5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3-ylmethoxy)phenyl]pyrazin-2-amine,5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4-ylmethoxy)phenyl]pyrazin-2-amine,4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide,2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide,5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H-tetrazol-5-yl)benzyl)oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine,(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)acetic acid,5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2-ylmethoxy)phenyl]pyrazin-2-amine,4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N,N-dimethyl-benzenesulfonamide,4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-methyl}-benzenesulfonamide,4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N-methylbenzenesulfonamide,5-{4-Cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(3-fluorobenzyl)oxy]phenyl}pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(2-fluorobenzyl)oxy]phenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(2,6-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(2,3-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-(3,4-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-{3-[(2-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-{3-[(3-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-{3-[(4-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(2,6-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(2,5-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(2,3-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(2,4-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(3,4-dimethylbenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine, 5-(3-{[2-Chloro-3-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine,5-(3-{[5-Chloro-2-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine,5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoicacid, 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}pyrazin-2-amine,5-{4-Cyclobutyl-3-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methoxy]-2-fluorophenyl}pyrazin-2-amine, tert-Butyl[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate,[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetic acid,racemic 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridin-2(1H)-one, racemic3-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrimidin-4(3H)-one, racemic2-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridazin-3(2H)-one, racemic1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrazin-2(1H)-one, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-5-ylamino)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-2-ylamino)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrazin-2-ylamino)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((5-aminopyrimidin-2-yl)amino)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((6-aminopyrimidin-4-yl)amino)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-pyrazol-1-yl)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-imidazol-1-yl)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,3-triazol-1-yl)propan-2-ol, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(2H-1,2,3-triazol-2-yl)propan-2-ol, racemic5-Amino-1-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile, racemic1-(5-Amino-1H-1,2,3-triazol-1-yl)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol, racemic1-((1H-Pyrazol-5-yl)amino)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol,5-(4-Cyclobutyl-2-fluoro-3-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}-phenyl)-pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)-oxy]-phenyl}pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl}pyrazin-2-amine,5-[4-Cyclobutyl-3-(cyclohexylmethoxy)-2-fluorophenyl]pyrazin-2-amine,5-[4-Cyclobutyl-3-(cyclopropylmethoxy)-2-fluorophenyl]pyrazin-2-amine,Ethyl 5-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylate, tert-Butyl4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-methyl}-piperidine-1-carboxylate,5-{4-Cyclobutyl-2-fluoro-3-[(3-methyl-1,2,4-oxadiazol-5-yl)-methoxy]-phenyl}-pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-methoxy-5-(pentafluoro-lambda~6~-sulfanyl)-benzyl]-oxy}-phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-5-(pentafluoro-lambda~6~-sulfanyl)benzyl]-oxy}-phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-4-(pentafluoro-lambda~6~-sulfanyl)benzyl]-oxy}-phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[4-(pentafluoro-lambda~6~-sulfanyl)benzyl]-oxy}-phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[3-(pentafluoro-lambda~6~-sulfanyl)benzyl]-oxy}-phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-(pentafluoro-lambda~6~-sulfanyl)benzyl]-oxy}-phenyl)-pyrazin-2-amine,5-[4-Cyclobutyl-3-(cyclobutylmethoxy)-2-fluorophenyl]pyrazin-2-amine,5-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine,4-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}benzoicacid,5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylic acid,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-4-amine,5-{4-Cyclobutyl-2-fluoro-3-[(4-phenylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine,5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(4-thiophen-2-ylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carbonitrile,5-{4-Cyclobutyl-2-fluoro-3-[(4-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(5-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methoxypyrimidin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methoxypyrimidin-4-amine,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile,5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine, Methyl4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoate,5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridazin-3-yl]oxy}phenyl)pyrazin-2-amine, Methyl6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylate,5-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile,3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile, 5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile,5-{4-Cyclobutyl-2-fluoro-3-[4-(pentafluoro-lambda~6~-sulfanyl)phenoxy]-phenyl}-pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[2-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine,5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine, 5-{3-[3,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine,5-{3-[(3-Chloropyridin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine, 5-{3-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine, 5-{4-Cyclobutyl-2-fluoro-3-[3-methyl-4-methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine,5-(4-cyclobutyl-2-fluoro-3-(4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy)-phenyl)-pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(3-methoxypyridin-2-yl)oxy]phenyl}pyrazin-2-amine,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5-(methylsulfonyl)-benzonitrile,5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)-3-(trifluoromethyl)-phenoxy]-phenyl}-pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(2-methylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[2-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine,5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine, 5-{3-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine trifluoroacetate salt,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methylpyrimidin-4-amine trifluoroacetate salt,5-{4-Cyclobutyl-3-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-fluorophenyl}pyrazin-2-amine,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-chloropyrimidin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(2-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(6-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine, 6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-benzylpyrimidin-4-amine,5-(4-Cyclobutyl-2-fluoro-3-{[6-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine,3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonitrile, tert-Butyl[2-({2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-yl}amino)ethyl]carbamate,N-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}ethane-1,2-diamine, Methyl 2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylate trifluoroacetate salt,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylic acid,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoic acid,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylic acid,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzamide,N′-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}-N,N-dimethylethane-1,2-diamine hydrochloride,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-5-amine, 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine,3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol,5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine,5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine, 4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine,5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrimidin-2-amine,5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine, 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrimidin-2-amine,4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine, 5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrimidin-2-amine,4-(3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isopropylpyrimidin-2-amine,2-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide, 5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine trifluoroacetate salt,6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-oltrifluoroacetate salt,6-Amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile,6-Amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile,3-{[3-(5-Amino-3-cyanopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid,2-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine,6-Cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol,2-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-5H-pyrrolo[2,3-b]pyrazine trifluoroacetate salt,2-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine,5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine hydrochloridesalt, 5-(4-Cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine,5-Methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoate,4-((3-(6-Aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoicacid,5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyrazine,6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine,7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol,7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile,7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile,7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide,4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide,7-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,(4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid,4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzoic acid,3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine,5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine,6-Cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol,3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenol,5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrazin-2-amine,5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine,2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine,5-{4-tert-Butyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine, 5-(4-tert-Butyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine,3-(2-Aminopyrimidin-5-yl)-6-tert-butyl-2-fluorophenol,5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrimidin-2-amine,5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine,5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine,5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine, 5-(4-Cyclopentyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine,5-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]pyrazin-2-amine,5-[4-Cyclopentyl-2-fluoro-3-(1-methylethoxy)phenyl]pyrazin-2-amine,2-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine,5-[3-(Benzyloxy)-4-tert-butylphenyl]pyrazin-2-amine,5-[3-(Benzyloxy)-4-cyclobutylphenyl]pyrazin-2-amine,3-amino-6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile,6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine,6-cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol,6-cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol,3-amino-6-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile,3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol,7-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,2-(6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine,7-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine,2-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine,2-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine,6-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridazin-3-amine,6-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyridazin-3-amine,6-(3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidin-4-ol,4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2-carbonitrile,6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,2-trimethylpyrimidin-4-amine,4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,6-trimethylpyrimidin-2-amine,6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N-dimethylpyrimidin-4-amine, Ethyl5-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate,5-(4-cyclobutyl-2-fluoro-3-((5-(methylsulfonyl)pyridin-2-yl)oxy)phenyl)pyrazin-2-amine,4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-(tert-butyl)pyrimidin-2-amine,5-(3-((4-(1,5-dioxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine,4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isobutylpyrimidin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine,N-(2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide,5-(4-Cyclobutyl-2-fluoro-3-(2-morpholinoethoxy)phenyl)pyrazin-2-amine,Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate,tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)-azetidine-1-carboxylate, tert-Butyl3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)-pyrrolidine-1-carboxylate, tert-Butyl2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)-pyrrolidine-1-carboxylate, tert-Butyl3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)-piperidine-1-carboxylate,2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethanol,4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoic acid,5-(4-Cyclobutyl-2-fluoro-3-((tetrahydrofuran-2-yl)methoxy)phenyl)pyrazin-2-amine, racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)-propan-2-ol, racemic3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propane-1,2-diol, racemic1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-morpholinopropan-2-ol, racemic4-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-thiomorpholine 1,1-dioxide,5-(4-Cyclobutyl-2-fluoro-3-(pyridazin-4-yloxy)phenyl)pyrazin-2-amine,3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-(pyrazin-2-yloxy)phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-4-yloxy)phenyl)pyrazin-2-amine,and4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N-isobutylpyrimidin-2-amine trifluoroacetic acid salt.

Particularly, an embodiment of the present invention comprises acompound selected from the compounds listed in Table 2.

TABLE 25-(4-Cyclobutyl-2-fluoro-3-{[2-(pentafluoro-lambda~6~-sulfanyl)benzyl]-oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[3-(pentafluoro-lambda~6~-sulfanyl)benzyl]-oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[4-(pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-4-(pentafluoro-lambda~6~-sulfanyl)-benzyl]oxy}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-flupro-5-(pentafluoro-lambda~6~-sulfanyl)benzyl]oxy-}phenyl)pyrazin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[2-methoxy-5-(pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile, 5-{4-Cyclobutyl-2-fluoro-3-[4-(pentafluoro-lambda~6~-sulfanyl)phenoxy]phenyl}pyrazin-2-amine,5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-4-amine,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine,5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine,5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}-pyrimidin-2-amine,5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}-pyrimidin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4- ol,4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methoxypyrimidin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methoxypyrimidin-4-amine,4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine,6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol trifluoroacetate,2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine, 5-{4-Cyclobutyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}-pyrazin-2-amine,5-{4-tert-Butyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}-pyrazin-2-amine,2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-5-amine,2-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide,5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}-pyrimidin-2-amine,5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}-pyrimidin-2-amine,5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine,5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine,and 6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine.

It is an embodiment of the present invention to provide a compoundselected from the compounds listed in Table 1A.

TABLE 1A 3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol,5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine,5-{3-[(2-Aminopyridin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-{3-[(6-Aminopyrazin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-5-yloxy)phenyl]pyrazin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-4-amine, 3-(5-Aminopyrazin-2-yl)-6-cyclonexyl-2-fluorophenol,3-(5-Aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenol,5-[4-Cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine,5-[4-Cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine,2-[3-(5-Aminopyrazin-2-yl)-6-cyclopentyl-2-fluorophenoxy]pyrimidin-4-amine, 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclopentyl-2-fluorophenyl}-pyrimidin-2-amine,6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-3-amine,5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-ylmethoxy)phenyl]pyrazin-2-amine,5-{3-[(4-Bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine,5-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)pyrimidin-2-amine,5-(4-Cyclobutyl-2-fluoro-3-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyrazin-2-amine,5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine,5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclonexyl-2-fluorophenyl}-pyrimidin-2-amine.

It is another embodiment of the present invention to provide a compoundselected from the compounds listed in Table 1, Table 2 and Table 1A.

The invention is also directed to a pharmaceutical composition whichinclude, without limitation, one or more of the disclosed compoundsherein, and pharmaceutically acceptable carriers or excipients.

Another embodiment of the present invention is a pharmaceuticalcomposition of the present invention that comprises at least a compoundselected from the compounds listed in Table 1. Another embodiment of thepresent invention is a pharmaceutical composition of the presentinvention that comprises at least a compound selected from the compoundslisted in Table 3.

Particularly, an embodiment of the present invention is a pharmaceuticalcomposition of the present invention that comprises at least a compoundselected from the compounds listed in Table 2.

The present invention also features a method of treating a subjectsuffering from or diagnosed with a disease and/or disorder mediated byFLAP activity, comprising administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I).

The present invention also features a method for preventing, treating,ameliorating, including without limitation inhibiting, the progressionof an FLAP-mediated disease and/or disorder in a subject in needthereof, comprising administering to said subject a therapeuticallyeffective amount of at least one compound of Formula (I). Such a diseaseand/or disorder includes, but is not limited to diabetes, respiratorydisorders, and associated symptoms or complications thereof. Morespecifically, this invention is directed to a method of treating, butnot limited to, exacerbations, non-allergic asthma, fibrotic lungdiseases, acute respiratory distress syndrome and chronic obstructivepulmonary disease, and their associated symptoms or complications, in asubject afflicted with such a disease and/or disorder.

In another embodiment, the compounds of the present invention are usefulfor the amelioration of symptoms associated with and/or the treatment ofthe following cardiac and cardiovascular diseases and/or disorders:myocardial infarction, atherosclerosis, atherosclerosis and strokeaortic aneurisms, or associated symptoms or complications thereof, in asubject afflicted with such a disease and/or disorder.

In another embodiment, the compounds of the present invention are usefulfor the amelioration of symptoms associated with and/or the treatment ofautoimmune or allergic diseases and/or disorders, wherein saidautoimmune or allergic diseases and/or disorders include, but are notlimited to, rheumatoid arthritis, inflammatory bowel disease, nephritis,spondyloarthritis, polymyositis, dermatomyositis, gouty effusions,systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease,multiple sclerosis, allergic rhinitis, allergic dermatitis and asthma,or associated symptoms or complications thereof, in a subject afflictedwith such a disease and/or disorder.

In a further embodiment, the compounds of the present invention areuseful for the amelioration of symptoms associated with and/or theprophylaxis or treatment of carcinogenesis, wherein said carcinogenesisinclude, but is not limited to, tumor cell proliferation,differentiation, apoptosis, tumor-associated angiogenesis, as well asthe migration and invasion of carcinoma cells.

It is a further embodiment of the invention to provide a process formaking a pharmaceutical composition comprising admixing any of thecompounds according to Formula (I) and a pharmaceutically acceptablecarrier.

In a further embodiment of the invention, a method for treating orameliorating an FLAP-mediated disease and/or disorder in a subject inneed thereof comprises administering to the subject a therapeuticallyeffective amount of at least one compound of Formula (I), wherein thetherapeutically effective amount of the compound of Formula (I) is fromabout 0.1 mg/dose to about 5 g/dose. In particular, the therapeuticallyeffective amount of the compound of Formula (I) is from about 0.5mg/dose to about 1000 mg/dose.

More particularly, the therapeutically effective amount of the compoundof Formula (I) is from about 1 mg/dose to about 100 mg/dose. In afurther embodiment of the invention, the number of doses per day of acompound of Formula (I) is from 1 to 3 doses. In a further embodiment ofthe invention, the therapeutically effective amount of the compound ofFormula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/day. Moreparticularly, the therapeutically effective amount of the compound ofFormula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day.

The invention is further described below.

A) Terms

Some terms are defined below and by their usage throughout thisdisclosure.

It should also be noted that any atom with unsatisfied valences in thetext, schemes, examples, structural formulae and any tables herein isassumed to have the hydrogen atom or atoms to satisfy the valences.

As used herein, the following terms are intended to have the followingdefinitions. The definitions herein may specify that a chemical term hasan indicated formula. The particular formula provided is not intended tolimit the scope of the invention, but is provided as an illustration ofthe term. The scope of the per se definition of the term is intended toinclude the plurality of variations expected to be included by one ofordinary skill in the art.

The term “C_(1-n)alkyl” means a saturated branched or straight-chainhydrocarbon radical having from 1 up to n carbon atoms, wherein n is 4or 5, in a linear or branched arrangement. Examples include methyl,ethyl, 1-propyl, 2-propyl, isobutyl, tert-butyl, isopentyl, neopentyl,pentan-3-yl, and the like, and all that are exemplified in the belowexamples. An alkyl radical may be attached to a core molecule by anyatom where allowed by available valences.

The term “C₃₋₆cycloalkyl” means a saturated or partially unsaturated,monocyclic, hydrocarbon ring system radical. Examples includecyclopropyl, cyclobutyl, cyclopentyl cyclohexyl and the like, and allthat are exemplified in the below examples. A C₃₋₅cycloalkyl radical maybe attached to a core molecule by any ring atom where allowed byavailable valences.

The term “aryl” means an unsaturated, aromatic monocyclic or polycyclichydrocarbon ring system radical. Examples include phenyl and the like,and all that are exemplified in the below examples. An aryl radical maybe attached to a core molecule by any ring atom where allowed byavailable valences.

The term “hetero”, when used as a prefix for a ring system, refers tothe replacement of at least one carbon atom member in the ring systemwith a heteroatom selected from N, O, S, S(O), or SO₂. A hetero ring mayhave 1, 2, 3 or 4 carbon atom members replaced by a nitrogen atom.Alternatively, a ring may have 1, 2 or 3 nitrogen atom members and 1oxygen or sulfur atom member. Alternatively, a ring may have 1 oxygen orsulfur atom member. Alternatively, up to two adjacent ring members maybe heteroatoms, wherein one heteroatom is nitrogen and the otherheteroatom is selected from N, S or O.

The term “heteroaryl” means an unsaturated monocyclic, polycyclicaromatic “hetero” ring system radical, selected from the groupconsisting of pyrazolyl, oxadiazolyl, furanyl, imidazolyl,imidazolidinyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl, quinazolinyl,benzothiazolyl, isoxazolyl, thiazolyl, oxazolyl, thiazolopyridyl,thienopyrimidinyl and isoindolyl. Examples include 1H-pyrazol-1-yl,1H-pyrazol-3-yl, 1H-pyrazol-5-yl, 1,2,4-oxadiazol-5-yl,1,2,4-oxadiazol-3-yl, furan-2-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl,1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazolidin-1-yl,1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-2-yl, 1H-1,2,4-triazol-3-yl,1H-1,2,4-triazol-4-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl,pyridin-3-yl, pyrimidin-1-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl,pyrazin-1-yl, pyrazin-2-yl, pyrazin-3-yl, benzimidazol-1-yl,benzoxazol-2-yl, quinoxalin-2-yl, quinazolin-2-yl, benzothiazol-2-yl,isoxazol-3-yl, 1,3-thiazol-4-yl, 1,3-oxazol-2-yl, isoindol-1-yl,thiazolo[4,5-b]pyridyl, thieno[2,3-d]pyrimidinyl and the like, and allthat are exemplified in the below examples. A heteroaryl radical may beattached to a core molecule by any ring atom where allowed by availablevalences.

The term “heterocyclyl” means a saturated monocyclic “hetero” ringsystem radical, selected from the group consisting of azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl,thiomorpholinyl, and tetrahydro-2H-pyranyl. Examples includeazetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, tetrahydrofuran-2-yl, morpholin-4-yl,thiomorpholin-4-yl, tetrahydro-2H-pyran-4-yl, and the like, and all thatare exemplified in the below examples. A heterocyclyl radical may beattached to a core molecule by any ring atom where allowed by availablevalences.

The term “carboxy” means a radical of the formula: —C(O)OH.

The term “halogen” or “halo” means a radical selected from the groupconsisting of chloro, bromo, fluoro or iodo.

The term “oxo” means a radical of the formula: ═O.

The term “substituted” refers to a radical in which one or more hydrogenatoms are each independently replaced with the same or differentsubstituent(s). In a preferred embodiment, up to three hydrogen atomsare each independently replaced.

With reference to substituents, the term “independently” means that whenmore than one of such substituent is possible, such substituents may bethe same or different from each other.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

In general, unless specified otherwise, IUPAC nomenclature rules areused herein.

The term “about,” whether used explicitly or not in reference to aquantitative expression given herein, means that every quantity givenherein qualified with the term or otherwise is meant to refer both tothe actual given value and the approximation to such given value thatwould reasonably be inferred based on the ordinary skill in the art,including approximations due to experimental and/or measurementconditions for such given value.

The term “form” means, in reference to compounds of the presentinvention, such may exist as, without limitation, a salt, stereoisomer,tautomer, crystalline, polymorph, amorphous, solvate, hydrate, ester,prodrug or metabolite form. The present invention encompasses all suchcompound forms and mixtures thereof.

The term “isolated form” means, in reference to compounds of the presentinvention, such may exist in an essentially pure state such as, withoutlimitation, an enantiomer, a racemic mixture, a geometric isomer (suchas a cis or trans stereoisomer), a mixture of geometric isomers, and thelike. The present invention encompasses all such compound forms andmixtures thereof.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “subject” as used herein, refers to a patient, such as ananimal, a mammal or a human, who has been the object of treatment,observation or experiment and is at risk of (or susceptible to)developing an FLAP-mediated disorder.

The term “administering” further means that the individual ingredientsto be combined may be administered at the same time or at differenttimes during the treatment period, either as one preparation or asdifferent preparations. Accordingly, the invention should be sointerpreted that it encompasses any and every administration mode at thesame time or at different times. The range of the combination of thecompound of the invention and the other therapeutic agent useful for theabove-mentioned disorders encompasses, in principle, all combinations ofthe compound of the invention and any and every pharmaceutical agentuseful for the above-mentioned disorders.

The term “treating” refers, without limitation, to facilitating theeradication of, preventing, ameliorating or otherwise inhibiting theprogression of or promoting stasis of an FLAP-mediated disease and/ordisorder, or associated symptoms or complications thereof.

The term “prodrug” means a compound of Formula (I) or a form thereofthat is converted in vivo into a functional derivative form that maycontribute to therapeutic biological activity, wherein the convertedform may be: 1) a relatively active form; 2) a relatively inactive form;3) a relatively less active form; or, 4) any form which results,directly or indirectly, from such in vivo conversions. Prodrugs areuseful when said compound may be either too toxic to administersystemically, absorbed poorly by the digestive tract or broken down bythe body before it reaches its target. Conventional procedures for theselection and preparation of suitable prodrug derivatives are describedin, for example, “Design of Prodruas”, ed. H. Bundgaard, Elsevier, 1985.

The term “metabolite” means a prodrug form of a compound of Formula (I)or a form thereof converted by in vivo metabolism or a metabolic processto a relatively less active functional derivative of said compound.

The term “medicament” or “medicine” refers to a product containing acompound of Formula (I) or a form thereof. The present inventionincludes use of such a medicament for treating an FLAP-mediateddisorder.

The term “combination form” refers to the use of a combination productcomprising a compound of Formula (I) or a form, pharmaceuticalcomposition, medicine or medicament thereof and at least one therapeuticagent for treating an FLAP-mediated disorder.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition.

For therapeutic purposes, the term “therapeutically effective amount” or“effective amount” as used herein, means that amount of each activecompound or pharmaceutical agent, alone or in combination, that elicitsthe biological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease and/or disorder being treated. For prophylactic purposes (i.e.,inhibiting the progression of a disorder), the term “therapeuticallyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that treats or inhibitsin a subject the progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician. Thus, thepresent invention provides combinations of two or more drugs wherein,for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both (ormore) drugs are administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together. The effective amount of saidcompound is from about 0.001 mg/kg/day to about 300 mg/kg/day.

Advantageously, the effective amount of a combination product fortreating an FLAP-mediated disease and/or disorder, or associatedsymptoms or complications thereof, may be a reduced amount of either orboth, the compound or therapeutic agent, compared to the effectiveamount of the compound or therapeutic agent otherwise recommended fortreating the disease and/or disorder, or associated symptoms orcomplications thereof. Therefore, it is contemplated that the compoundis administered to the subject before, during or after the time theagent is administered.

The term “pharmaceutically acceptable salt” refers to non-toxicpharmaceutically acceptable salts (Ref. Int'l J. Pharm., 1986, 33:201-217; J. Pharm. Sci., 1997 (January), 66(1): 1). Other salts wellknown to those in the art may, however, be useful in the preparation ofcompounds according to this invention or of their pharmaceuticallyacceptable salts. Representative organic or inorganic acids include, butare not limited to, hydrochloric, hydrobromic, hydriodic, perchloric,sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic,succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The compounds of the invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the“pharmaceutically acceptable salts” of the compounds of this inventionrefer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable salt forms include acid addition salts which may, for example,be formed by mixing a solution of the compound according to theinvention with a solution of an acid such as acetic acid, adipic acid,benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid,hydrochloric acid, maleic acid, malonic acid, phosphoric acid,saccharinic acid, succinic acid, sulphuric acid, tartaric acid,trifluoroacetic acid and the like.

Furthermore when the compounds of the present invention carry an acidicmoiety, suitable salts thereof may include alkali metal salts, e.g.sodium or potassium salts; alkaline earth metal salts, e.g. calcium ormagnesium salts; and salts formed with suitable organic ligands, e.g.quaternary ammonium salts.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Edition, John Wiley & Sons, 1999.The protecting groups may be removed at a convenient subsequent stageusing methods known in the art. The scope of the present inventionencompasses all such protected compound forms and mixtures thereof.

The invention includes compounds of various isomers and mixturesthereof. The term “isomer” refers to compounds that have the samecomposition and molecular weight but differ in physical and/or chemicalproperties. Such substances have the same number and kind of atoms butdiffer in structure. The structural difference may be in constitution(geometric isomers) or in an ability to rotate the plane of polarizedlight (optical isomers).

The term “stereoisomer” refers to isomers that have the same molecularformula and the same sequence of covalently bonded atoms but a differentspatial orientation.

The term “optical isomer” means isomers of identical constitution thatdiffer only in the spatial arrangement of their groups. Optical isomersrotate the plane of polarized light in different directions. The term“optical activity” means the degree to which an optical isomer rotatesthe plane of polarized light.

The term “racemate” or “racemic” means an equimolar mixture of twoenantiomeric species, wherein each of the isolated species rotates theplane of polarized light in the opposite direction such that the mixtureis devoid of optical activity.

The term “enantiomer” means an isomer having a nonsuperimposable mirrorimage. The term “diastereomer” means stereoisomers that are notenantiomers.

The term “chiral” means a molecule that, in a given configuration,cannot be superimposed on its mirror image. This is in contrast toachiral molecules that can be superimposed on their mirror images.

The two distinct mirror image versions of the chiral molecule are alsoknown as levo (left-handed), abbreviated L, or dextro (right-handed),abbreviated D, depending on which way they rotate polarized light. Thesymbols “R” and “S” represent the configuration of groups around astereogenic carbon atom(s).

The term “geometric isomer” means isomers that differ in the orientationof substituent atoms in relationship to a carbon-carbon double bond, toa cycloalkyl ring, or to a bridged bicyclic system. Substituent atoms(other than hydrogen) on each side of a carbon-carbon double bond may bein an E or Z configuration according to the Cahn-Ingold-Prelog priorityrules. In the “E” configuration, the substituents having the highestpriorities are on opposite sides in relationship to the carbon-carbondouble bond. In the “Z” configuration, the substituents having thehighest priorities are oriented on the same side in relationship to thecarbon-carbon double bond.

Substituent atoms (other than hydrogen) attached to a ring system may bein a “cis” or “trans” configuration. In the “cis” configuration, thesubstituents are on the same side in relationship to the plane of thering; in the “trans” configuration, the substituents are on oppositesides in relationship to the plane of the ring. Compounds having amixture of “cis” and “trans” species are designated “cis/trans”.

The isomeric descriptors (“R,” “S,” “E,” and “Z”) indicate atomconfigurations and are intended to be used as defined in the literature.

The compounds of the invention may be prepared as individual isomers byeither isomer-specific synthesis or resolved from an isomeric mixture.Conventional resolution techniques include combining the free base (orfree acid) of each isomer of an isomeric pair using an optically activeacid (or base) to form an optically active salt (followed by fractionalcrystallization and regeneration of the free base), forming an ester oramide of each of the isomers of an isomeric pair by reaction with anappropriate chiral auxiliary (followed by fractional crystallization orchromatographic separation and removal of the chiral auxiliary), orseparating an isomeric mixture of either an intermediate or a finalproduct using various well known chromatographic methods.

Furthermore, compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and, as such, are intended tobe included in the scope of the invention. In addition, some of thecompounds may form solvates with water (i.e., hydrates) or commonorganic solvents (e.g., organic esters such as ethanolate and the like)and, as such, are also intended to be encompassed within the scope ofthis invention.

B) Compounds

Representative compounds of the present invention are listed in Table 3below.

TABLE 3 COM- POUND STRUCTURE # NAME

A 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

B 3-(5-Aminopyrazin-2-yl)-6-cyclobutyl- 2-fluorophenol

1 5-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)benzyl]oxy}phenyl)-pyrazin-2-amine

2 5-(4-Cyclobutyl-2-fluoro-3-{[3- (trifluoromethyl)benzyl]oxy}phenyl)-pyrazin-2-amine

3 5-(4-Cyclobutyl-2-fluoro-3-{[2- (trifluoromethyl)benzyl]oxy}phenyl)-pyrazin-2-amine

4 3-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

5 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

6 5-(4-Cyclobutyl-2-fluoro-3-{[3- (methylsulfonyl)benzyl]oxy}phenyl)-pyrazin-2-amine

7 5-(4-Cyclobutyl-2-fluoro-3-{[4- (methylsulfonyl)benzyl]oxy}phenyl)-pyrazin-2-amine

8 5-(4-Cyclobutyl-2-fluoro-3-{[2- (trifluoromethoxy)benzyl]oxy}phenyl)-pyrazin-2-amine

9 5-(4-Cyclobutyl-2-fluoro-3-{[3- (trifluoromethoxy)benzyl]oxy}phenyl)-pyrazin-2-amine

10 5-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethoxy)benzy]oxy}phenyl)-pyrazin-2-amine

11 5-(3-{[4-Chloro-2- (methylsulfonyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2- amine

12 1-(4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}phenyl)ethanone

13 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3-ylmethoxy)phenyl]pyrazin-2-amine

14 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4-ylmethoxy)phenyl]pyrazin-2-amine

15 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

16 3-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

17 3-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzamide

18 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

19 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzamide

20 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H- tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

21 5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H- tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

22 5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H- tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

23 (4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}phenyl)acetic acid

24 5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2-ylmethoxy)phenyl]pyrazin-2-amine

25 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}-N,N-dimethylbenzenesulfonamide

26 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzenesulfon- amide

27 4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}-N-methylbenzenesulfonamide

28 5-{4-Cyclobutyl-2-fluoro-3-[(4- fluorobenzyl)oxy]phenyl}pyrazin-2-amine

29 5-{4-Cyclobutyl-2-fluoro-3-[(3- fluorobenzyl)oxy]phenyl}pyrazin-2-amine

30 5-{4-Cyclobutyl-2-fluoro-3-[(2- fluorobenzyl)oxy]phenyl}pyrazin-2-amine

31 5-{4-Cyclobutyl-3-[(2,6- difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

32 5-{4-Cyclobutyl-3-[(2,3- difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

33 5-{4-Cyclobutyl-3-[(3,4- difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

34 5-{3-[(2-Chlorobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2-amine

35 5-{3-[(3-Chlorobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2-amine

36 5-{3-[(4-Chlorobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2-amine

37 5-{4-Cyclobutyl-3-[(2,6- dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

38 5-{4-Cyclobutyl-3-[(2,5- dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

39 5-{4-Cyclobutyl-3-[(2,3- dichlorobenzy)oxy]-2-fluorophenyl}pyrazin-2-amine

40 5-{4-Cyclobutyl-3-[(2,4- dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

41 5-{4-Cyclobutyl-3-[(3,4- dimethybenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

42 5-(3-{[2-Chloro-3- (trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2- amine

43 5-(3-{[5-Chloro-2- (trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2- amine

44 5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro- 2-(trifluoromethyl)benzyl]oxy}phenyl) pyrazin-2-amine

45 5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

46 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

47 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-pyrazol-3-yl)methoxy]phenyl}pyrazin-2-amine

48 5-{4-Cyclobutyl-3-[(3-cyclopropyl- 1,2,4-oxadiazol-5-yl)methoxy]-2-fluorophenyl}pyrazin-2-amine

49 tert-Butyl [3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate

50 [3-(5-Aminopyrazin-2-yl)-6-cyclobutyl- 2-fluorophenoxy]acetic acid

51 racemic 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyridin-2(1H)-one

52 racemic 3-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyrimidin-4(3H)-one

53 racemic 2-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyridazin-3(2H)-one

54 racemic 1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)pyrazin-2(1H)one

55 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-5-ylamino)propan-2-ol

56 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-2-ylamino)propan-2-ol

57 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(pyrazin-2-ylamino)propan-2-ol

58 racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((5- aminopyrimidin-2-ylamino)propan-2- ol

59 racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((6- aminopyrimidin-4-yl)amino)propan-2-ol

60 racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- pyrazol-1-yl)propan-2-ol

61 racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- imidazol-1-yl)propan-2-ol

62 racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- 1,2,4-triazol-1-yl)propan-2-ol

63 racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H- 1,2,3-triazol-1-yl)propan-2-ol

64 racemic 1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(2H- 1,2,3-triazol-2-yl)propan-2-ol

65 racemic 5-Amino-1-(3-(3-(5- aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-1H- pyrazole-4-carbonitrile

66 racemic 1-(5-Amino-1H-1,2,3-triazol-1-yl)-3-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)propan-2-ol

67 racemic 1-((1H-Pyrazol-5-yl)amino)- 3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2- ol

68 5-(4-Cyclobutyl-2-fluoro-3-{[1- (methylsulfonyl)piperidin-4-yl]methoxy}phenyl)pyrazin-2-amine

69 5-{4-Cyclobutyl-2-fluoro-3-[(4- methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

70 racemic 5-{4-Cyclobutyl-2-fluoro-3- [(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl}pyrazin-2-amine

71 5-[4-Cyclobutyl-3- (cyclohexylmethoxy)-2-fluorophenyl]pyrazin-2-amine

72 5-[4-Cyclobutyl-3- (cyclopropylmethoxy)-2-fluorophenyl]pyrazin-2-amine

73 Ethyl 5-{[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}furan-2- carboxylate

74 tert-Butyl 4-{[3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2-fluorophenoxy]methyl}piperidine-1- carboxylate

75 5-{4-Cyclobutyl-2-fluoro-3-[(3-methyl- 1,2,4-oxadiazol-5-yl)methoxy]phenyl}pyrazin-2-amine

76 5-(4-Cyclobutyl-2-fluoro-3-{[2- methoxy-5-(pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

77 5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro- 5-(pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

78 5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro- 4-(pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

79 5-(4-Cyclobutyl-2-fluoro-3-{[4- (pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

80 5-(4-Cyclobutyl-2-fluoro-3-{[3- (pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

81 5-(4-Cyclobutyl-2-fluoro-3-{[2- (pentafluoro-lambda~6~-sulfanyl)benzyl]oxy}phenyl)pyrazin-2- amine

82 5-[4-Cyclobutyl-3- (cyclobutylmethoxy)-2-fluorophenyl]pyrazin-2-amine

83 5-[3-(Benzyloxy)-4-cyclobutyl-2- fluorophenyl]-pyrazin-2-amine

84 4-{2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]ethyl}benzoic acid

85 5-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}furan-2- carboxylic acid

86 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-4-amine

87 5-{4-Cyclobutyl-2-fluoro-3-[(4- phenylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

88 5-(4-Cyclobutyl-2-fluoro-3-{[4- (methylsulfanyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

89 5-{4-Cyclobutyl-3-[(4,6- dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

90 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1- methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

91 5-{4-Cyclobutyl-2-fluoro-3-[(4- thiophen-2-ylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

92 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidine-4- carbonitrile

93 5-{4-Cyclobutyl-2-fluoro-3-[(4- methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

94 5-{4-Cyclobutyl-2-fluoro-3-[(5- methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

95 5-(4-Cyclobutyl-2-fluoro-3-{[4- (methylsulfonyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

96 4-[3-(5-Aminopyrazin-2-y)-6- cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine

97 5-{4-Cyclobutyl-2-fluoro-3-[(6- methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

98 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol

99 4-[3-(5-Aminopyrazin-2-y)-6- cyclobutyl-2-fluorophenoxy]-6-methoxypyrimidin-2-amine

100 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-2-methoxypyrimidin-4-amine

101 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]benzonitrile

102 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

103 Methyl 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoate

104 5-(4-Cyclobutyl-2-fluoro-3-{[5- (trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

105 5-(4-Cyclobutyl-2-fluoro-3-{[5- (trifluoromethyl)pyrazin-2-yl]oxy}phenyl)pyrazin-2-amine

106 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridazin-3-yl]oxy}phenyl)pyrazin-2-amine

107 Methyl 6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine- 3-carboxylate

108 5-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

109 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

110 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

111 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

112 3-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

113 5-(4-Cyclobutyl-2-fluoro-3-{[5- (trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

114 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

115 5-{4-Cyclobutyl-2-fluoro-3-[4- (pentafluoro-lambda~6~-sulfanyl)phenoxy]phenyl}pyrazin-2- amine

116 5-{4-Cyclobutyl-2-fluoro-3-[4- (methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

117 5-{4-Cyclobutyl-2-fluoro-3-[2- (methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

118 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

119 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine

120 5-{3-[3,4- Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

121 5-(4-Cyclobutyl-2-fluoro-3-{[3- (trifluoromethy)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

122 5-{3-[(3-Chloropyridin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

123 5-{3-[2-Chloro-4- (methylsulfonyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

124 5-(4-Cyclobutyl-2-fluoro-3-{[2- (trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

125 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

126 5-{4-Cyclobutyl-2-fluoro-3-[3-methyl- 4-(methylsulfonyl)phenoxy]phenyl} pyrazin-2-amine

127 5-(4-cyclobutyl-2-fluoro-3-(4- (methylsulfonyl)-2-(trifluoromethyl)phenoxy)phenyl) pyrazin-2-amine

128 5-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridin-3-yl]oxy}phenyl)pyrazin-2-amine

129 5-{4-Cyclobutyl-2-fluoro-3-[(3- methoxypyridin-2-yl)oxy]phenyl}pyrazin-2-amine

130 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine

131 5-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

132 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-5-(methylsulfonyl)benzonitrile

133 5-{4-Cyclobutyl-2-fluoro-3-[4- (methylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl} pyrazin-2-amine

134 5-{4-Cyclobutyl-2-fluoro-3-[(2- methylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

135 5-(4-Cyclobutyl-2-fluoro-3-{[2-(1- methylethy)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

136 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine

137 5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

138 5-{3-[(6-Azetidin-1-ylpyrimidin-4- yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine trifluoroacetate salt

139 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-N,N-dimethyl-2-(trifluoromethy)pyrimidin- 4-amine

140 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-2-methylpyrimidin-4-amine trifluoroacetate salt

141 5-{4-Cyclobutyl-3-[(6- cyclopropylpyrimidin-4-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

142 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

143 4-[3-(5-Aminopyrazin-2-yl)-6- cycloloutyl-2-fluorophenoxy]-6-chloropyrlmidin-2-amine

144 5-{4-Cyclobutyl-2-fluoro-3-[(2- phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

145 5-{4-Cyclobutyl-2-fluoro-3-[(6- phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

146 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-2-benzylpyrimidin-4-amine

147 5-(4-Cyclobutyl-2-fluoro-3-{[6-(1- methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

148 3-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4- carbonitrile

149 tert-Butyl [2-({2-[3-(5-aminopyrazin-2- yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4- yl}amino)ethyl]carbamate

150 N-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin- 2-yl}ethane-1,2-diamine

151 Methyl 2-[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidine-4- carboxylate trifluoroacetate salt

152 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylic acid

153 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]benzoicacid

154 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylic acid

155 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2- fluorophenoxy]benzamide

156 N′-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}-N,N-dimethylethane-1,2-diamine hydrochloride

157 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidine-4- carboxamide

158 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidin-5-amine

159 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)pyrimidin-2-amine

E 3-(2-Aminopyrimidin-5-yl)-6- cyclobutyl-2-fluorophenol

160 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

161 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2- amine

162 4-[3-(2-Aminopyrimn-5-yl)-6- cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

163 5-{4-Cyclobutyl-2-fluoro-3-[(4- methylpyrimidin-2-yl)oxy]phenyl}pyrimidin-2-amine

164 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2- amine

165 5-(4-Cyclobutyl-2-fluoro-3-{[4-(1- methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrimidin-2-amine

166 4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin- 2-amine

167 5-{4-Cyclobutyl-3-[(4,6- dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pynmidin-2-amine

168 4-(3-(2-aminopyrimidin-5-yl)-6- cyclobutyl-2-fluorophenoxy)-6-isopropylpyrimidin-2-amine

169 2-[3-(2-Aminopyrimidin-5-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidine-4- carboxamide

170 5-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine trifluoroacetate salt

171 6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin- 4-ol trifluoroacetate

172 6-Amino-3-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)pyrazine-2-carbonitrile

173 6-Amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

174 3-{[3-(5-Amine-3-cyanopyrazin-2-yl)- 6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

175 2-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine

F 6-Cyclobutyl-2-fluoro-3-(5H- pyrrolo[2,3-b]pyrazin-2-yl)phenol

176 2-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)benzyl]oxy}phenyl)-5H-pyrrolo[2,3-b]pyrazine trifluoroacetate salt

177 2-[3-(Benzyloxy)-4-cyclobutyl-2- fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine

178 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)pyridin-2-aminehydrochloride salt

179 5-(4-Cyclobutyl-2-fluoro-3- hydroxyphenyl)pyridin-2-amine

180 5-Methyl-4-((3-(6-aminopyridin-3-yl)- 6-cyclobutyl-2-fluorophenoxy)methyl)benzoate

181 4-((3-(6-Aminopyridin-3-yl)-6- cyclobutyl-2-fluorophenoxy)methyl)benzoic acid

182 5-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)-1H-imidazo[4,5-b]pyrazine

183 6-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-3H-imidazo[4,5-b]pyridine

184 7-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

185 6-Cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol

186 7-[3-(Benzyloxy)-4-cyclobutyl-2- fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

187 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzonitrile

188 7-(4-Cyclobutyl-2-fluoro-3-{[3- (methylsulfonyl)-benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine

189 7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)-benzyl]-oxy}-phenyl)- 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

190 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzonitrile

191 7-(4-Cyclobutyl-2-fluoro-3-{[4- (trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine

192 3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzamide

193 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]-methyl}-benzamide

194 7-(4-Cyclobutyl-2-fluoro-3-{[6- (trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine

195 (4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}phenyl)aceticacid

196 4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2- fluorophenoxy]methyl}benzoic acid

197 3-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine

198 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

199 6-Cyclobutyl-3-(2,3-dihydro-1H- pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol

G 3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2- fluorophenol

200 5-(4-tert-Butyl-3-{[tert- butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrazin-2-amine

201 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

202 6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4- amine

203 2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4- amine

204 5-{4-tert-Butyl-2-fluoro-3-[(6- methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

205 5-(4-tert-Butyl-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

H 3-(2-Aminopyrimidin-5-yl)-6-tert-butyl- 2-fluorophenol

206 5-(4-tert-Butyl-3-{[tert- butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrimidin-2-amine

207 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

208 5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2- amine

209 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2- amine

210 5-(4-Bromo-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

211 5-(4-Cyclopentyl-2-fluoro-3- methoxyphenyl)pyrazin-2-amine

212 5-[3-(Benzyloxy)-4-cyclopentyl-2- fluorophenyl]pyrazin-2-amine

213 5-[4-Cyclopentyl-2-fluoro-3-(1- methylethoxy)phenyl]pyrazin-2-amine

214 2-[3-(Benzyloxy)-4-cyclopentyl-2- fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine

215 5-[3-(Benzyloxy)-4-tert- butylphenyl]pyrazin-2-amine

216 5-[3-(Benzyloxy)-4-chloro-2- fluorophenyl]pyrazin-2-amine

217 5-[3-(Benzyloxy)-4- cyclobutylphenyl]pyrazin-2-amine

218 3-amino-6-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)pyrazine-2-carbonitrile

219 6-(4-cyclobutyl-2-fluoro-3- methoxyphenyl)pyridazin-3-amine

220 6-cyclobutyl-2-fluoro-3-(1H- pyrrolo[2,3-b]pyridin-5-yl)phenol

221 6-cyclobutyl-2-fluoro-3-(7H- pyrrolo[2,3-c]pyridazin-3-yl)phenol

222 3-amino-6-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

223 3-(6-aminopyridazin-3-yl)-6- cyclobutyl-2-fluorophenol

224 5,5′-((pyrimidine-2,4- diylbis(oxy))bis(4-cyclobutyl-2-fluoro-3,1-phenylene))bis(pyrazin-2-amine

225 7-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazine

226 2-(6-cyclobutyl-3-(3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine

227 7-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2- b][1,4]oxazine

228 5-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine

229 2-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine

230 2-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)pheny)-5H-pyrrolo[2,3- b]pyrazine

231 6-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridazin-3-amine

232 6-(4-cyclobutyl-2-fluoro-3-((6- methoxypyrimidin-4-yl)oxy)phenyl)pyridazin-3-amine

233 6-(3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidin- 4-ol

234 4-(3-(5-Amnopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)pyrimidine-2- carbonitrile

235 6-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N,N,2-trimethylpyrimidin-4-amine

236 4-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N,N,6-trimethylpyrimidin-2-amine

237 6-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N,N-dimethylpyrimidin-4-amine

238 Ethyl 5-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-1-methyl- 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

239 5-(4-cyclobutyl-2-fluoro-3-((5- (methylsulfonyl)pyridin-2-yl)oxy)phenyl)pyrazin-2-amine

240 4-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-6-(tert-butyl)pyrimidin-2-amine

241 5-(3-((4-(1,5-dioxa-9- azaspiro[5.5]undecan-9-yl)pyrimidin-2-yl)oxy)-4-cyclobutyl-2- fluorophenyl)pyrazin-2-amine

242 4-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-6-isobutylpyrimidin-2-amine

I 5-(4-Cyclobutyl-2-fluoro-3- methoxyphenyl)-1H-pyrrolo[2,3- b]pyridine

243 N-(2-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide

244 5-(4-Cyclobutyl-2-fluoro-3-(2- morpholinoethoxy)phenyl)pyrazin-2-amine

245 Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate

246 tert-Butyl 3-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2-fluorophenoxy)methyl)azetidine-1- carboxylate

247 tert-Butyl 3-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1- carboxylate

248 tert-Butyl 2-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1- carboxylate

249 tert-Butyl 3-((3-(5-aminopyrazin-2-yl)- 6-cyclobutyl-2-fluorophenoxy)methyl)piperidine-1- carboxylate

250 2-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)ethanol

251 4-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)butanoicacid

252 5-(4-Cyclobutyl-2-fluoro-3- ((tetrahydrofuran-2-yl)methoxy)phenyl)pyrazin-2-amine

253 racemic 1-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)propan-2-ol

254 racemic 3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propane- 1,2-diol

255 racemic 1-(3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-3-morpholinopropan-2-ol

256 racemic 4-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2- hydroxypropyl)thiomorpholine 1,1-dioxide

257 5-(4-Cyclobutyl-2-fluoro-3-(pyridazin-4-yloxy)phenyl)pyrazin-2-amine

258 3-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)pyrazin-2-amine

259 5-(4-Cyclobutyl-2-fluoro-3-(pyrazin-2- yloxy)phenyl)pyrazin-2-amine

260 5-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-4-yloxy)phenyl)pyrazin-2-amine

261 4-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)-N-isobutylpyrimidin-2-amine trifluoroacetic acid salt

262 Methyl 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}- 1,3-benzoxazole-5-carboxylate

263 Methyl 3-({[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]acetyl}amino)-4- hydroxybenzoate

264 5-[4-Cyclobutyl-2-fluoro-3-(tetrahydro- 2H-pyran-4-ylmethoxy)phenyl]pyrazin-2-amine

265 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3-(methylsulfonyl)benzonitrile

266 5-{3-[2,4- Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

267 5-{4-Cyclobutyl-3-[3- (dimethylamino)propoxy]-2-fluorophenyl}pyrazin-2-amine

268 5-{4-Cyclobutyl-3-[2- (dimethylamino)ethoxy]-2-fluorophenyl}pyrazin-2-amine

269 4-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-N,6-dimethylpyrimidin-2-amine

270 2-[6-Cyclobutyl-2-fluoro-3-(7H- pyrrolo[2,3-c]pyridazin-3-yl)phenoxy]pyrimidin-4-amine

271 5-{4-Cyclobutyl-3-[(6,7- difluoroquinoxalin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

272 2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]quinazolin-4-amine

273 2-Amino-5-[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyrimidine-4- carbonitrile

274 Methyl 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}- 1,3-benzoxazole-5-carboxylate

275 Methyl 3-({[3-(5-aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]acetyl}amino)-4- hydroxybenzoate

276 [3-(5-Aminopyrazin-2-yl)-6-cyclobutyl- 2-fluorophenoxy]acetonitrile

277 5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-yloxy)phenyl]pyrazin-2-amine

278 5-[4-Cyclopropyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

279 2-[3-(5-Aminopyrazin-2-yl)-6- cyclopropyl-2-fluorophenoxy]pyrimidin-4-amine

280 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-imidazol-2-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

281 Methyl 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}- 1,3-oxazole-4-carboxylatetrifluoroacetic acid salt

282 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}-1,3-oxazole-4-carboxylic acid trifluoroacetic acid salt

283 5-[3-(1,3-Benzothiazol-2-ylmethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2- amine trifluoroacetic acid salt

284 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-imidazol-4-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

285 5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl- 1H-imidazol-5-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

286 2-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}pyridine-3- carbonitrile trifluoroacetic acid salt

287 5-{4-Cyclobutyl-2-fluoro-3-[(2-methyl- 1,3-thiazol-4-yl)methoxyl]phenyl}pyrazin-2-amine trifluoroacetic acid salt

288 5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-ylmethoxy)phenyl]pyrazin-2-amine trifluoroacetic acid salt

289 5-{3-[(5-Chloropyridin-2-yl)methoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine trifluoroacetic acid salt

290 5-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}pyridine-2- carbonitrile trifluoroacetic acid salt

291 5-{4-Cyclobutyl-2-fluoro-3-[(5- methylisoxazol-3-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetic acid salt

292 6-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}pyridine-2- carbonitrile trifluoroacetic acid salt

293 2-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}-1H- isoindole-1,3(2H)-dione

294 5-[3-(2-Aminoethoxy)-4-cyclobutyl-2- fluorophenyl]pyrazin-2-amine

295 5-{4-Cyclobutyl-2-fluoro-3-[2-(pyrazin-2-ylamino)ethoxy]phenyl}pyrazin-2- amine trifluoroacetic acid salt

296 N-{2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-2- amine trifluoroacetic acid salt

297 N-{2-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-4- amine

298 5-[4-Cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl]pyrazin-2-amine hydrogen chloride salt

299 racemic 5-[4-Cyclobutyl-2-fluoro-3- (piperidin-3-ylmethoxy)phenyl]pyrazin-2-amine

300 racemic 5-[4-Cyclobutyl-2-fluoro-3- (pyrrolidin-3-ylmethoxy)phenyl]pyrazin-2-amine

301 5-[3-(Azetidin-3-ylmethoxy)-4- cyclobutyl-2-fluorophenyl]pyrazin-2-amine

302 racemic 5-[4-Cyclobutyl-2-fluoro-3- (pyrrolidin-2-ylmethoxy)phenyl]pyrazin-2-amine

303 racemic 5 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3- piperidin-1-ylpropan-2-ol

304 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3-(methylamino)propan-2-ol

305 racemic 1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-[(1- methylethyl)amino]propan-2-ol

306 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3-pyrrolidin-1-ylpropan-2-ol

307 racemic 1-[3-(5-Aminopyrazin-2-yl)-6-cycloloutyl-2-fluorophenoxy]-3- (dimethylamino)propan-2-ol

308 diastereomeric mixture 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2- fluorophenoxy]-2-hydroxypropyl}pyrrolidin-3-ol

309 racemic 1-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-3-piperazin-1-ylpropan-2-ol

310 racemic 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2- hydroxypropyl}pyrimidin-2(1H)-one

311 racemic 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2- hydroxypropyl}-1,3-dihydro-2H-benzimidazol-2-one

312 racemic 1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2- hydroxypropyl}imidazolidin-2-one

313 2′-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]-5,5′-bipyrimidin-2-amine

314 5-[2-Fluoro-4-methyl-3-(pyrimidin-2- yloxy)phenyl]pyrazin-2-amine

315 2-[3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenoxy]pyrimidin-4-amine

316 5-[4-Ethyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl]pyrazin-2-amine

317 2-[3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenoxy]pyrimidin-4-amine

318 5-[2-Fluoro-4-(1-methylethyl)-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2- amine

319 5-[2-Fluoro-4-propyl-3-(pyrimidin-2- yloxy)phenyl]pyrazin-2-amine

320 5-(4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

321 5-(4-(Cyclohexylmethyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2- amine

322 5-(2-Fluoro-4-isopentyl-3-(pyrimidin- 2-yloxy)phenyl)pyrazin-2-amine

323 5-(2-Fluoro-4-isobutyl-3-(pyrimidin-2- yloxy)phenyl)pyrazin-2-amine

324 5-(2-Fluoro-4-neopentyl-3-(pyrimidin- 2-yloxy)pheny)pyrazin-2-amine

325 2-(3-(5-Aminopyrazin-2-yl)-6- cyclohexyl-2-fluorophenoxy)pyrimidin-4-amine

326 2-(3-(5-Aminopyrazin-2-yl)-6- (cyclohexylmethyl)-2-fluorophenoxy)pyrimidin-4-amine

327 2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isopentylphenoxy)pyrimidin-4-amine

328 2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isobutylphenoxy)pyrimidin-4-amine

329 5-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)pyrimidine-2- carboxamide

330 5-(4-Cyclobutyl-2-fluoro-3- (thiazolo[4,5-b]pyridin-2-yloxy)phenyl)pyrazin-2-amine

331 5-(4-Cyclobutyl-2-fluoro-3- ((5-methylthieno[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrazin-2-amine

332 N⁴-(2-(3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy)ethyl)pyrimidine-2,4- diamine

333 3-(5-Aminopyrazin-2-yl)-6-ethyl-2- fluorophenol

334 5-[4-Cyclopentyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

335 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclopentyl-2-fluorophenyl}pyrimidin- 2-amine

336 2-[3-(5-Aminopyrazin-2-yl)-6- cyclopentyl-2-fluorophenoxy]pyrimidin-4-amine

337 5-[4-Cyclopentyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

338 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridazin-3-amine

339 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-ylmethoxy)phenyl]pyrazin-2-amine

340 5-{3-[(4-Bromobenzyl)oxy]-4- cyclobutyl-2-fluorophenyl}pyrazin-2-amine

341 5-(4-{[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]methyl}phenyl)pyrimidin- 2-amine

342 5-(4-Cyclobutyl-2-fluoro-3-{[4′- (trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyrazin-2-amine

343 5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

344 5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclohexyl-2-fluorophenyl}pyrimidin- 2-amine

345 3-(5-Aminopyrazin-2-yl)-6-cyclohexyl- 2-fluorophenol

346 3-(5-Aminopyrazin-2-yl)-6- (cyclohexylmethyl)-2-fluorophenol

347 5-{3-[(2-Aminopyridin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

348 5-{3-[(6-Aminopyrazin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2- amine

349 5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-5-yloxy)phenyl]pyrazin-2-amine

350 6-[3-(5-Aminopyrazin-2-yl)-6- cyclobutyl-2-fluorophenoxy]pyridazin-4-amine

351 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3- b]pyridineC) Synthesis

The invention provides methods of making the disclosed compoundsaccording to traditional organic synthetic methods as well as matrix orcombinatorial synthetic methods. Scheme A described suggested syntheticroutes. Using the schemes, the guidelines below, and the examples, aperson of skill in the art may develop analogous or similar methods fora given compound that is within the invention. These methods arerepresentative of the synthetic schemes, but are not to be construed aslimiting the scope of the invention.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, geometric isomers, and enantiomers thereof areencompassed within the scope of the present invention.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic schemes described below and areillustrated more particularly in the specific synthetic examples thatfollow. The general schemes are offered by way of illustration; theinvention should not be construed as being limited by the chemicalreactions and conditions expressed. The methods for preparing thevarious starting materials used in the schemes and examples are wellwithin the skill of persons versed in the art. No attempt has been madeto optimize the yields obtained in any of the example reactions. Oneskilled in the art would know how to increase such yields throughroutine variations in reaction times, temperatures, solvents and/orreagents.

General: ¹H and ¹³C NMR spectra were measured on a Bruker AC-300 (300MHz) spectrometer using tetramethylsilane and the deuterated solventrespectively as internal standards. Elemental analyses were obtained byQuantitative Technologies Inc. (Whitehouse, N.J.) and the results werewithin 0.4% of the calculated values unless otherwise mentioned. Meltingpoints were determined in open capillary tubes with a Mel-Temp IIapparatus (Laboratory Devices Inc.) and were uncorrected. Electrospraymass spectra (MS-ESI) were recorded in the positive mode on a HewlettPackard 59987A spectrometer. High resolution mass spectra (HRMS) wereobtained on a Micromass Autospec. E spectrometer by fast atombombardment (FAB) technique.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Examples of the described synthetic routes include Scheme A,Intermediates A-N, Examples 1-351 and prophetic Examples 1-36. Compoundsanalogous to the target compounds of these examples can be madeaccording to similar routes. The disclosed compounds are useful aspharmaceutical agents as described herein.

Abbreviations or acronyms used herein include:

Abbreviation Meaning BOC/boc tert-butyloxycarbonyl BOPbenzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateCDCl₃ deuterated chloroform Cpd compound DCE dichloroethane DCMdichloromethane DMAP dimethylaminopyridine DIPEA diisopropyl ethyl amineDMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethylsulfoxide DPBS Dulbecco's phosphate buffered saline EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ESIElectrospray Ionization Et₃N or TEA triethylamine Et₂O diethyl etherEtOAc ethyl acetate h/hr/hrs hour(s) HOBT 1-hydroxybenzotriazole hydrateHBTU O-benzotriazol-1-yloxy-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxid hexafluorophosphate LG Leaving group LiOH lithium hydroxide MeCNAcetonitrile MeOH methanol min minute(s) MS mass spectroscopy NMRnuclear magnetic resonance spectroscopy OTf Triflate PG protecting groupRT/rt room temperature TBME tert-Butyl-methyl ether TFA trifluoro aceticacid THF tetrahydrofuran TLC thin layer chromatography Tosp-toluenesulfonyl MgSO₄ Magnesium sulfate EtOH Ethanol BBr₃ BorontribromideGeneral Guidance

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are illustrations, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art. The substituents forcompounds of Formula (I) or a form thereof, represented in the schemesbelow, are as previously defined herein.

Unless otherwise specified, reaction solutions were stirred at roomtemperature under a N_(2(g)) or Ar_((g)) atmosphere. When solutions were“concentrated to dryness”, they were concentrated using a rotaryevaporator under reduced pressure, when solutions were dried, they aretypically dried over a drying agent such as magnesium sulfate (MgSO₄) orsodium sulfate (Na₂SO₄).

Normal phase flash column chromatography (FCC) was performed on silicagel with RediSep® silica gel columns using ethyl acetate(EtOAc)/hexanes, CH₂Cl₂/MeOH, CH₂Cl₂/10% 2 N NH₃ in MeOH, CH₂Cl₂/i-PrOH,and the like as eluent, unless otherwise indicated.

Reverse phase high performance liquid chromatography (HPLC) wasperformed under the following conditions: 1) Instrument, Shimadzu;Column, Waters XBridge C18 10 μM (250×50 mm), Phenomenex Gemini column 5μm C18 (150×21.2 mm) or Waters Xterra RP18 OBD 5 μm (100×30 mm);Gradient, 95:5 to 0:100 water (0.05% trifluoroacetic acid (TFA))/CH₃CN(0.05% TFA); Flow rate, 30-80 mL/min; Detection, UV at λ=220-254 nM; 2)Instrument, Gilson; Column, Phenomenex LUNA column 5 μm C18 (250×50 mm)or Waters XBridge Prep C18 OBD 5 μm (30×150 mm); Gradient, 95:5 to 0:100water (0.05% TFA)/CH₃CN (0.05% TFA); Flow rate, 30-80 mL/min; Detection,UV at λ=220-254 nM; 3) Instrument, Gilson/Shimadzu: Column, InertsilODS-3 column (30×100 mm) or Inertsil ODS-3 (30×50 mm, 5 μm); Gradient,water-acetonitrile with both phases with 0.05% by volume trifluoroaceticacid; 1 min hold at 5% ACN, then 6 min gradient to 99% ACN followed by ahold at that concentration for 3 min. Flow rate, 80 ml/min; heatedcolumn at 46° Celsius with detection of UV light at λ=254 nm; and 4)Instrument, Dionex: UVD 170U Diode array detector and ThermoFinneganSurveyor MSQ plus mass spectrometer for data collection. Waters XBridgeC18 5 μM OBD 50×100 mm prep column. All runs utilized water acetonitrilewith 20 mM NH₄OH added to the aqueous phase and a flow rate for allgradients was 80 mL/min using four possible gradients: 1) 5-60% MeCNover 12 min, then ramped to 100% MeCN and held for 6.3 min; 2) 30-70%MeCN over 12 min, then ramped to 100% MeCN and held for 6.3 min; 3)50-80% MeCN over 12 min, then ramped to 100% MeCN and held for 6.3 min;and 4) 60-100% MeCN over 12 min, and then held for 6.3 min. The totalrun time for all gradient systems was 18.5 min.

Instances where solutions were filtered through a syringe filter, Pall0.45 μM GHP membrane 13 mm and 25 mm diameter syringe filters were used.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone. Microwave reactions were carried out ineither a CEM Discover® or a Biotage Initiator™ or Optimizer™ microwaveat specified temperatures. Mass spectra were obtained on an Agilentseries 1100 MSD using electrospray ionization (ESI) in positive modeunless otherwise indicated. Calculated mass corresponds to the exactmass. NMR spectra were obtained on either a Bruker model DPX400 (400MHz), DPX500 (500 MHz), DRX600 (600 MHz) spectrometer. The format of the¹H NMR data below is: chemical shift in ppm down field of thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration).

Hydrochloride salts were obtained by treating the corresponding freebases with HCl (4 N in dioxane, 2 M in Et₂O, or 1.25 N in MeOH) at roomtemperature with mixtures and then either concentrated to obtain the HClsalt, or the resulting solid being isolated by filtration.Trifluoroacetic acid salts were obtained by purification of the crudereaction product by preparative reverse phase HPLC, whereby the finalproducts were isolated as either mono-, di- or tri trifluoroacetic acidsalts.

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ACD/Name Version 10.01 (Advanced Chemistry).

The compounds of Formula (I), wherein ring A, L, R₁, R₂, R₃, R₄ and R₅are defined as in Formula (I), may be synthesized as outlined by thegeneral synthetic route illustrated in Scheme A.

Referring to Scheme A, compounds of Formulae (XIII) can be prepared fromappropriately substituted phenols (X) wherein the phenol (—OP) isprotected as either an alkyl or alkyl and aryl silyl ether. Protectedphenols, as the methyl ether, can be prepared by known methods or can beobtained commercially. Compounds (X), where W is a hydrogen and X iseither bromo or chloro, can be converted to the corresponding boronicacid (XIV) via directed ortho-metallation (DOM) using bases such as LDA,and lithium tetramethyl piperidide (LTMP) (either made in situ orobtained from commercial sources) and triisopropyl borate in solventssuch as THF, DME, ether and mixtures thereof at temperatures rangingfrom ⁻78-0° Celsius. In compounds of formulae (XIV) where X is bromo orchloro and Z is fluoro or hydrogen, compound (XV) can be obtained viasequential Pd cross-coupling reactions to install Ar¹ followed by Y.Preferred solvents for cross-coupling reactions were conducted in asolvent, such as DME, DMSO, DMF, DMA, dioxane, THF, EtOH or toluene, ormixtures of the aforementioned solvents, with or without added water inthe presence of a base, such as Na₂CO₃, K₂CO₃, KOAc, KH₂PO₄, K₂HPO₄, orK₃PO₄, using a palladium catalysts, such as Pd(dppf)Cl₂.CH₂Cl₂,palladium(II) trifluoroacetate and Ph₃P,chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]-palladium(II),1,1′-bis[di-t-butylphosphino)ferrocene]-palladium(II) chloride withtemperatures ranging from room temperature to 120° Celsius.

Additionally, compounds of formulae (XI) where W is hydrogen, Z iseither H or fluoro, and Y is alkyl or cycloalkyl can be formed fromcompound (X), where X is bromo, via metal halogen exchange usingalkyllithium or alkylmagnesium halide reagents, such as nBuLi ori-PrMgCl, in solvents such as di-ethyl ether or THF at temperaturesranging from ⁻78° Celsius to room temperature followed by treatment withan electrophile. In those instances wherein a ketone is used as theelectrophile, such as cyclobutanone or cyclopentanone, reduction of theresulting hydroxyl group can be achieved using known methods such asEt₃SiH in DCM in the presence of TFA. Alternatively, compound offormulae (XI) can be obtained through use of a palladium catalyst, suchas palladium(II) acetate, with an added ligand, such as2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl, to couple (X) toan alkyl or arylzinc reagent, such as cyclobutylzinc bromide, in asolvent, such as THF, at temperatures ranging from rt to 100° Celsius.Compound of formulae (XI) can be further elaborated to those of formulae(XII), using previously described methods such as DOM, borylation, andPd mediated cross-coupling. Compounds of formulae (X) in which X isalkyl, aryl or heteroaryl can be converted to compounds of formulae(XII) or (XV) through DOM, borylation, and Pd mediated cross-couplingusing methods.

Compounds of formulae (XIII) can be obtained from those of formulae(XII) or (XV) by first removing the silyl protecting group using afluoride source, such as TBAF or CsF in solvents such as THF, followedby subjecting the resultant phenol to S_(N)2 or S_(N)Ar reactionconditions in the presence of a suitable electrophile and solvents suchas DMF, DMSO and DMA in the presence of bases such as K₂CO₃, Cs₂CO₃.Na₂CO₃, and K₂PO₄ at temperatures ranging from 0-140° Celsius.Alternatively, compounds of formulae (XIII) can prepared viaintermediates of formulae (XII) and (XV) wherein P is a methyl group.Removal of the methyl group can be achieved using known methods.Preferred methods for removal of methyl ethers include BBr₃ in DCM attemperatures ranging from ³¹ 78° Celsius to 0° Celsius. Compounds offormulae (XIII) are formed using suitable electrophiles such as variousalkyl, aryl, and heteroaryl halides in the presence of bases such asK₂CO₃ or Cs₂CO₃ with or without the presence of cation chelation agents,such as 18-crown-6, in solvents such as DMSO, DMA, ACN, DMF and mixturesthereof at temperatures ranging from 0-140° Celsius using eitherconventional or microwave heating.

EXAMPLES

The following examples are offered by way of illustration; the inventionshould not be construed as being limited by the chemical reactions andconditions expressed.

Intermediate A

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

Step A: 1-(3-Fluoro-2-methoxyphenyl)cyclobutanol

To a 500 mL round-bottomed flask were added a stir bar,2-bromo-6-fluoroanisol (11.03 g, 53.8 mmol) and dry THF (215 mL). Theflask was purged with nitrogen and cooled to 0° Celsius before adding2.0 M i-PrMgCl in THF (60 mL, 120 mmol) over the course of 3 min. Theresultant mixture was stirred for 2 h before adding cyclobutanone (5.0mL, 67 mmol). The resultant mixture was stirred for 0.5 hour beforediluting with Et₂O (500 mL) and washing with saturated NH₄Cl followed bybrine. The organic layer was isolated, dried over MgSO₄, filtered andconcentrated to dryness to give a pale-yellow oil. Subjecting theresidue to FCC yielded 1-(3-fluoro-2-methoxyphenyl)cyclobutanol as apale-yellow oil (5.18 g, 49%). ¹H NMR (600 MHz, CDCl₃) δ 7.07-7.03 (m,1H), 7.03-6.98 (m, 1H), 6.98-6.94 (m, 1H), 3.99 (d, J=2.4, 3H), 3.39 (s,1H), 2.57-2.45 (m, 2H), 2.41-2.31 (m, 2H), 2.17-2.05 (m, 1H), 1.75-1.65(m, 1H).

Step B: 1-Cyclobutyl-3-fluoro-2-methoxybenzene

To a 500 mL round-bottomed flask were added a stir bar,1-(3-fluoro-2-methoxyphenyl)cyclobutanol (5.21 g, 26.6 mmol), dry DCM(250 mL), Et₃SiH (39.0 mL, 244 mmol) and TFA (20 mL, 260 mmol). Theresultant mixture was stirred at rt for 22 h before concentrating todryness and subjecting the residue to FCC to give1-cyclobutyl-3-fluoro-2-methoxybenzene as a pale-yellow oil (3.78 g,79%). ¹H NMR (600 MHz, CDCl₃) δ 7.03-6.99 (m, 1H), 6.99-6.95 (m, 1H),6.91 (m, 1H), 3.86 (d, J=1.6, 3H), 3.83-3.72 (m, 1H), 2.39-2.28 (m, 2H),2.19-2.07 (m, 2H), 2.07-1.98 (m, 1H), 1.89-1.80 (m, 1H).

Step C: (4-Cyclobutyl-2-fluoro-3-methoxyphenyl)boronic Acid

To a 500 mL round-bottomed flask were added a stir bar, dry THF (60 mL)and 2,2,6,6-tetramethylpiperidine (8.0 mL, 47 mmol). The flask wascooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi inhexanes (18.0 mL, 45 mmol) over 2 min. The resultant mixture was stirredfor 5 min and then allowed to warm to 0° C. After 35 min, the mixturewas re-cooled to −78° Celsius and treated with B(O-iPr)₃ (10.20 mL, 44mmol) over 4 min. After 16 min, a solution consisting of1-cyclobutyl-3-fluoro-2-methoxybenzene (7.24 g, 40.2 mmol) and dry THF(20.0 mL) was added over the course of 6 min and stirring continued for3.5 h before adding HOAc (8 mL). The mixture was then poured into waterand stirred for 5 min. The aqueous mixture was then extracted with EtOAc(200 mL), the extract dried over MgSO₄, filtered and concentrated todryness to give (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid asan off-white solid (8.08 g, 90%). The crude product was used directly inthe next synthetic step.

Step D: 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

To a 1000 mL round-bottom flask were added a stir bar,2-amino-5-bromopyrazine (19.95 g, 115.3 mmol),(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (25.0 g, 112 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (5.92 g, 7.28 mmol) and K₂CO₃ (47.33 g, 343 mmol).The flask was flushed with nitrogen and then charged with spargedtoluene (97 mL), sparged water (97 mL) and sparged DMF (61 mL). Thereaction vessel was heated at 80° Celsius for 17 hours before cooling toroom temperature. The reaction mixture was filtered and the filtrate wasconcentrated to dryness. The residue was extracted with EtOAc (200mL×3), the combined extracts dried over MgSO₄, filtered and concentratedto dryness. The residue was subjected to FCC to give the title compound(29.68 g). MS (ESI): mass calcd. for C₁₅H₁₆FN₃O, 273.13; m/z found,274.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.32-8.26 (dd, J=2.5, 1.5,1H), 8.02-7.96 (d, J=1.5, 1H), 7.54-7.47 (m, 1H), 7.20-7.14 (m, 1H),6.65 (s, 2H), 3.87-3.79 (d, J=1.0, 3H), 3.79-3.68 (m, 1H), 2.34-2.24 (m,2H), 2.17-2.06 (m, 2H), 2.06-1.94 (m, 1H), 1.87-1.76 (m, 1H).

Intermediate B

3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol

Method 1:

Step A: 1-(3-Fluoro-2-methoxyphenyl)cyclobutanol

To a 3-L round-bottom flask were added a stir bar,2-bromo-6-fluoroanisol (75.00 g, 370 mmol) and dry THF (1460 mL). Theflask was purged with nitrogen and cooled to 0° Celsius before adding2.0 M i-PrMgCl in THF (408 mL, 916 mmol) over the course of 15 min. Theresultant mixture was stirred for 2 hours before adding cyclobutanone(34 mL, 455 mmol). The resultant mixture was stirred for 0.5 hour beforediluting with Et₂O (2.50 L) and washing with saturated NH₄Cl followed bybrine. The organic layer was isolated, dried over MgSO₄, filtered andconcentrated to dryness to give the crude product. Subjecting theresidue to FCC gave the title compound (55.58 g). ¹H NMR (400 MHz,CDCl₃) δ 6.98-6.88 (m, 3H), 3.90-3.90 (s, 3H), 2.46-2.42 (m, 2H),2.31-2.28 (m, 2H), 2.04 (m, 1H), 1.67-1.64 (m, 1H).

Step B: 1-Cyclobutyl-3-fluoro-2-methoxybenzene

To a 3-L round-bottom flask were added a stir bar,1-(3-fluoro-2-methoxyphenyl)-cyclobutanol (80.17 g, 410 mmol), dry DCM(1231 mL), Et₃SiH (200 mL, 1.23 mol) and TFA (93 mL, 1.2 mmol). Theresultant mixture was stirred at rt for 22 h before concentrating todryness and subjecting the residue to FCC to give1-cyclobutyl-3-fluoro-2-methoxybenzene as a pale-yellow oil (51.90 g,70.5%). ¹HNMR (400 MHz, CDCl₃) δ 7.07-6.93 (m, 3H), 3.91 (s, 3H),3.85-3.81 (m, 1H), 2.40-2.36 (m, 2H), 2.20-2.07 (m, 3H), 1.91-1.88 (m,1H).

Step C: (4-Cyclobutyl-2-fluoro-3-methoxyphenyl)boronic Acid

To a 500 mL round-bottom flask were added a stir bar, dry THF (83 mL)and 2,2,6,6-tetramethylpiperidine (11 mL, 65 mmol). The flask was cooledto −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (25mL, 62.5 mmol) over 2 min. The resultant mixture was stirred for 5 minand then allowed to warm to 0° C. After 35 min, the mixture wasre-cooled to −78° Celsius and treated with B(O-iPr)₃ (14 mL, 60 mmol)over 4 min. After 16 min, a solution consisting of1-cyclobutyl-3-fluoro-2-methoxybenzene (10.0 g, 55.6 mmol) and dry THF(27 mL) was added over the course of 6 min and stirring continued for3.5 hours before adding saturated NH₄Cl (200 mL). The mixture was thenpoured into water and stirred for 5 min. The aqueous mixture was thenextracted with EtOAc (200 mL×3), the combined extracts dried over MgSO₄,filtered and concentrated to dryness to give the crude product as anoff-white solid. The crude product was subjected to FCC to give thetitle compound (7.21 g). ¹HNMR (400 MHz, CD₃OD): δ 7.11-7.07 (m, 2H),3.38 (s, 3H), 3.82-3.80 (m, 1H), 2.37-2.33 (m, 2H), 2.19-2.11 (m, 3H),2.09-1.90 (m, 1H).

Step D: 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

To a 1000 mL round-bottom flask were added a stir bar,2-amino-5-bromopyrazine (19.95 g, 115.3 mmol),(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (25.0 g, 112 mmol),Pd(dppf)Cl₂.CH₂Cl₂ (5.92 g, 7.28 mmol) and K₂CO₃ (47.33 g, 343 mmol).The flask was flushed with nitrogen and then charged with spargedtoluene (97 mL), sparged water (97 mL) and sparged DMF (61 mL). Thereaction vessel was heated at 80° Celsius for 17 hours before cooling toroom temperature. The reaction mixture was filtered and the filtrate wasconcentrated to dryness. The residue was extracted with EtOAc (200mL×3), the combined extracts dried over MgSO₄, filtered and concentratedto dryness. The residue was subjected to FCC to give the title compound(29.68 g). MS (ESI): mass calcd. for C₁₅H₁₆FN₃O, 273.13; m/z found,273.9 [M+H]⁺.

Step E

To a 3 L round-bottom flask were added a stir bar,5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine (29.68 g, 121.0mmol) and dry DCM (1190 mL). The flask was purged with nitrogen, stirreduntil homogeneous and cooled to −78° Celsius. Once cool, the flask wascharged with 1.0 M BBr₃ in DCM (364 mL, 364 mmol). After 3 hours, thereaction mixture was warmed to room temperature and stirred for anadditional 2 hours. The reaction mixture was then poured carefully intoa flask containing ice (300 mL) and saturated NaHCO₃ resulting in theappearance of a tan ppt. The resultant mixture was subjected to vacuumfiltration to give pure title compound as a tan solid (86%). ¹H NMR (400MHz, CD₃OD), δ 8.29 (s, 1H), 8.04 (s, 1H), 7.21-7.17 (m, 1H), 7.08-7.05(d, J=8.4, 1H), 3.87-3.78 (m, 1H), 2.40-2.34 (m, 2H), 2.23-2.12 (m, 2H),2.10-2.01 (m, 1H), 1.91-1.85 (m, 1H).

Method 2:

Step A: (2-Bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane

A 500-mL three-neck, round bottomed flask, equipped with a stir bar,temperature probe and nitrogen inlet, was charged with2-bromo-6-fluorophenol (25 g, 130.9 mmol, 1.00 eq), DMF (252 mL, 0.52M), imidazole (12.3 g, 181 mmol, 1.38 eq) and tertbutyldimethylsilylchloride (19.7 g, 131 mmol, 1.00 eq). The mixture was heated at 60°Celsius for 3 hours. The reaction was cooled to room temperature anddiluted with water. The aqueous phase was extracted with ethyl acetateand the resultant organic solution washed with water and brine and driedover sodium sulfate. The organic phase was concentrated to dryness andpurified using FCC to provide(2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane as a colorless oil(33 g, 82%).

Step B: (2-Cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane

A 1-L three-neck, round bottomed flask, equipped with a stir bar,temperature probe and nitrogen inlet was charged with(2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (27.2 g, 89.1 mmol),THF (181.2 mL) and bis(tri-tert-butylphosphine)palladium (3.4 g, 6.68mmol). Cyclobutylzinc bromide (267.2 mL, 134 mmol) was added and thereaction is heated at 45° Celsius for 22 hours. The reaction was cooledto room temperature and quenched with 1M HCl. The aqueous phase isextracted with MTBE and the combined organic extracts were washed withwater, saturated aqueous thiourea, 1M HCl brine, dried over sodiumsulfate and concentrated to dryness to provide(2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane as a lightyellow oil (24.5 g, 98%). MS (EI): calcd. for C₁₆H₂₅FOSi, 280.5; m/zfound 280.1 [M]. ¹H NMR (400 MHz, CDCl₃), δ 7.08-7.04 (m, 1H), 6.90-6.83(m, 2H), 3.81 (tt, J=9.4, 7.8 Hz, 1H), 2.32 (dtd, J=10.3, 7.8, 2.4 Hz,2H), 2.14-1.80 (m, 4H), 1.03 (s, 9H), 0.20 (s, 3H), 0.19 (s, 3H).

Step C:(3-((tert-Butyldimethylsilyl)oxy)-4-cyclobutyl-2-fluorophenyl)boronicAcid

A 100 mL three neck round-bottomed flask, equipped with a stir bar,temperature probe and nitrogen inlet, was charged with2,2,6,6-tetramethylpiperidine (1.7 mL, 10 mmol) and THF (10 mL). Themixture was cooled to −78° Celsius and treated with 2.5 M n-BuLi (4.1mL, 10 mmol). The resultant mixture was stirred for 5 min and thenwarmed up to 0° Celsius for 40 min. After 40 min the reaction mixturewas cooled to −78° Celsius and treated with B(O-^(i)Pr)₃ (13.0 mL, 10.2mmol) over the course of 10 min. After stirring for 20 min a solution of(2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane (1.8 g, 6.3mmol) in THF (4 mL) was added over the course of 2 min. The reaction wasstirred at −78° Celsius for 2 hours and then warmed to 0° Celsius.Acetic acid (3.6 mL, 64 mmol) is added and the reaction was warmed toroom temperature and diluted with water. The resultant mixture wasextracted with ethyl acetate. The organic portion was dried over sodiumsulfate and concentrated to dryness to provide(3-((tert-butyldimethylsilyl)-oxy)-4-cyclobutyl-2-fluorophenyl)boronicacid (1.8 g, 86%). ¹H NMR (500 MHz, CDCl₃), δ 7.39-7.32 (m, 1H),7.18-7.13 (m, 1H), 5.10-4.97 (m, 2H), 3.82 (t, J=8.8 Hz, 1H), 2.41-2.06(m, 5H), 2.03-1.95 (m, 1H), 1.03 (s, 9H), 0.19 (s, 6H).

Step D: 3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol

A 50 mL three-neck flask, equipped with a stir bar, nitrogen inlet andtemperature probe, was charged with(3-((tert-butyldimethylsilyl)oxy)-4-cyclobutyl-2-fluorophenyl)boronicacid (1.7 g, 5.3 mmol), toluene (4.7 mL), DMF (2.8 mL) and water (4.7mL). The solvent mixture was sparged for 30 minutes and then treatedwith 2-amino-5-bromopyrazine (923 mg, 5.3 mmol), potassium carbonate(2.19 g, 15.8 mmol) anddichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II).CH₂Cl₂ (137mg, 0.17 mmol). The reaction mixture was heated at 80° Celsius for 24hours. The reaction mixture was then cooled to room temperature, dilutedwith water (8 mL) and the stirred for two hours. The precipitate wascollected by filtration and dried in a vacuum oven at 60° Celsiusovernight to give 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol(1.2 g, 87%). MS (ESI+) Calcd. for C₁₄H₁₄FN₃O, 260.3; m/z found 260.1[M+H]⁺. ¹H NMR (400 MHz, DMSO), δ 8.24 (m, 1H), 7.98 (d, J=1.5 Hz, 1H),7.09 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.57 (s, 2H), 3.81-3.72 (m, 1H),2.34-2.14 (m, 2H), 2.14-1.69 (m, 4H).

Example 1

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

To a 15 mL round-bottomed flask were added a stir bar,3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (51 mg, 0.20 mmol),4-trifluoromethylbenzyl bromide (52 mg, 0.22 mmol), powdered KOH (42 mg,0.75 mmol) and DMSO (2.0 mL). The resultant mixture was stirred at roomtemperature for 22.5 hours before diluting with 100 mL EtOAc and washingwith water (×3). The organic layer was isolated, dried, filtered, andconcentrated to dryness. The crude product was subjected to FCC to givethe title compound as a pale-yellow solid (54 mg, 66%). MS (ESI): masscalcd. for C₂₂H₁₉F₄N₃O, 417.15; m/z found, 418.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.36-8.26 (dd, J=2.5, 1.4, 1H), 8.02-7.99 (d, J=1.5,1H), 7.82-7.76 (dd, J=8.8, 0.9, 2H), 7.74-7.68 (m, 2H), 7.59-7.51 (m,1H), 7.26-7.19 (d, J=8.3, 1H), 6.68 (s, 2H), 5.12 (s, 2H), 3.79-3.69 (p,J=8.9, 1H), 2.26-2.16 (m, 2H), 2.14-2.04 (m, 2H), 2.00-1.88 (m, 1H),1.83-1.73 (m, 1H).

Example 2

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 3-trifluoromethylbenzyl bromide. MS (ESI): mass calcd.for C₂₂H₁₉F₄N₃O, 417.15; m/z found, 418.1 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD) δ 8.25 (s, 2H), 7.82-7.78 (d, J=2.0, 1H), 7.76-7.70 (d, J=7.5,1H), 7.69-7.64 (d, J=7.9, 1H), 7.63-7.56 (m, 2H), 7.26-7.20 (m, 1H),5.17 (s, 2H), 3.83-3.72 (m, 1H), 2.33-2.22 (m, 2H), 2.21-2.10 (m, 2H),2.07-1.96 (m, 1H), 1.90-1.80 (m, 1H).

Example 3

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 2-trifluoromethylbenzyl bromide. MS (ESI): mass calcd.for C₂₂H₁₉F₄N₃O, 417.15; m/z found, 418.1 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD) δ 8.29-8.22 (m, 2H), 7.92-7.86 (d, J=7.7, 1H), 7.79-7.74 (m, 1H),7.73-7.68 (m, 1H), 7.65-7.59 (m, 1H), 7.58-7.53 (m, 1H), 7.29-7.22 (m,1H), 5.23 (s, 2H), 3.86-3.72 (m, 1H), 2.30-2.20 (m, 2H), 2.20-2.07 (m,2H), 2.05-1.91 (m, 1H), 1.90-1.78 (m, 1H).

Example 4

3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoicAcid

The title compound was prepared using analogous conditions described inExample 1 using 3-(bromomethyl)benzoic acid. MS (ESI): mass calcd. forC₂₂H₂₀FN₃O₃, 393.15; m/z found, 394.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.32-8.24 (m, 1H), 8.21-8.12 (dd, J=12.3, 1.6, 2H), 8.06-7.98 (m, 1H),7.73-7.66 (m, 1H), 7.59-7.48 (m, 2H), 7.24-7.19 (d, J=8.2, 1H), 5.13 (s,2H), 3.85-3.75 (m, 1H), 2.28 (m, 2H), 2.20-2.08 (m, 2H), 2.07-1.96 (m,1H), 1.90-1.80 (m, 1H).

Example 5

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoicAcid

The title compound was prepared using analogous conditions described inExample 1 using 4-(bromomethyl)benzoic acid. MS (ESI): mass calcd. forC₂₂H₂₀FN₃O₃, 393.42; m/z found, 394.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.37-8.31 (d, J=1.5, 1H), 8.23 (s, 1H), 8.09-8.04 (d, J=8.2, 2H),7.66-7.60 (m, 1H), 7.60-7.56 (d, J=8.0, 2H), 7.27-7.21 (d, J=8.4, 1H),5.14 (s, 2H), 3.87-3.74 (p, J=8.7, 1H), 2.35-2.22 (m, 2H), 2.20-2.09 (m,2H), 2.09-1.97 (m, 1H), 1.89-1.82 (m, 1H).

Example 6

5-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 1-(bromomethyl)-3-(methylsulfonyl)benzene. MS (ESI):mass calcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) 8.34-8.29 (dd, J=2.3, 1.4, 1H), 8.08-8.03 (m, 1H),8.03-7.99 (d, J=1.5, 1H), 7.96-7.91 (m, 1H), 7.87-7.82 (m, 1H),7.75-7.69 (m, 1H), 7.58-7.52 (m, 1H), 7.25-7.20 (d, J=8.3, 1H), 6.71 (s,2H), 5.15 (s, 2H), 3.80-3.69 (m, 1H), 3.24 (s, 3H), 2.28-2.16 (m, 2H),2.14-2.03 (m, 2H), 2.02-1.89 (m, 1H), 1.86-1.74 (m, 1H).

Example 7

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 1-(bromomethyl)-4-(methylsulfonyl)benzene. MS (ESI):mass calcd. for C₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 8.36-8.27 (m, 1H), 8.05-7.95 (m, 3H), 7.81-7.72 (m,2H), 7.61-7.51 (m, 1H), 7.27-7.18 (d, J=8.2, 1H), 5.13 (s, 2H),3.81-3.71 (m, 1H), 3.24 (s, 3H), 2.27-2.18 (m, 2H), 2.15-2.05 (m, 2H),2.02-1.92 (m, 1H), 1.85-1.74 (m, 1H).

Example 8

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 1-(bromomethyl)-2-(trifluoromethoxy)benzene. MS (ESI):mass calcd. for C₂₂H₁₉F₄N₃O₂, 433.14; m/z found, 434.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 8.33-8.27 (dd, J=2.3, 1.4, 1H), 8.05-8.01 (m, 1H),7.73-7.68 (dd, J=7.6, 1.8, 1H), 7.59-7.51 (m, 2H), 7.51-7.41 (m, 2H),7.25-7.20 (d, J=8.2, 1H), 5.07 (s, 2H), 3.78-3.58 (m, 1H), 2.23-2.12 (m,2H), 2.12-2.01 (m, 2H), 1.96-1.86 (m, 1H), 1.82-1.73 (m, 1H).

Example 9

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 1-(bromomethyl)-3-(trifluoromethoxy)benzene. MS (ESI):mass calcd. for C₂₂H₁₉F₄N₃O₂, 433.14; m/z found, 434.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 8.33-8.28 (m, 1H), 8.06-8.01 (m, 1H), 7.59-7.52 (m,2H), 7.52-7.45 (m, 2H), 7.40-7.33 (m, 1H), 7.24-7.18 (d, J=8.2, 1H),5.09 (s, 2H), 3.77-3.64 (p, J=8.9, 1H), 2.24-2.14 (m, 2H), 2.13-2.01 (m,2H), 1.98-1.86 (m, 1H), 1.83-1.72 (m, 1H).

Example 10

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 1-(bromomethyl)-4-(trifluoromethoxy)benzene. MS (ESI):mass calcd. for C₂₂H₁₉F₄N₃O₂, 433.14; m/z found, 434.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 8.33-8.28 (m, 1H), 8.06-8.01 (m, 1H), 7.63-7.58 (m,2H), 7.57-7.52 (m, 1H), 7.45-7.39 (m, 2H), 7.24-7.20 (d, J=8.2, 1H),5.04 (s, 2H), 3.76-3.65 (m, 1H), 2.24-2.14 (m, 2H), 2.12-2.02 (m, 2H),1.99-1.88 (m, 1H), 1.82-1.72 (m, 1H).

Example 11

5-(3-{[4-Chloro-2-(methylsulfonyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 1-(bromomethyl)-4-chloro-2-(methylsulfonyl)benzene. MS(ESI): mass calcd. for C₂₂H₂₁ClFN₃O₃S, 461.10; m/z found, 462.1 [M+H]⁺.¹H NMR (600 MHz, DMSO-d₆) δ 8.30-8.26 (m, 1H), 8.03-8.00 (dd, J=2.9,1.5, 1H), 8.00-7.97 (d, J=1.7, 1H), 7.95-7.91 (m, 2H), 7.61-7.56 (m,1H), 7.28-7.23 (d, J=8.3, 1H), 5.45 (s, 2H), 3.83-3.73 (m, 1H), 3.36 (s,3H), 2.28-2.18 (m, 2H), 2.16-2.04 (m, 2H), 2.01-1.89 (m, 1H), 1.84-1.75(m, 1H).

Example 12

1-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)ethanone

The title compound was prepared using analogous conditions described inExample 1 using 1-(4-(bromomethyl)phenyl)ethanone. MS (ESI): mass calcd.for C₂₃H₂₂FN₃O₂, 391.17; m/z found, 392.1 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 8.33-8.29 (m, 1H), 8.05-7.98 (m, 3H), 7.66-7.61 (m, 2H),7.57-7.52 (m, 1H), 7.24-7.20 (d, J=8.2, 1H), 5.45 (s, 2H), 3.81-3.78 (m,1H), 2.61 (s, 3H), 2.28-2.16 (m, 2H), 2.14-2.03 (m, 2H), 1.99-1.89 (m,1H), 1.84-1.75 (m, 1H).

Example 13

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 3-chloromethylpyridine. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O, 350.15; m/z found, 351.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ9.03-8.97 (d, J=2.1, 1H), 8.88-8.82 (dd, J=5.3, 1.5, 1H), 8.71-8.65 (m,1H), 8.28-8.23 (m, 1H), 8.22-8.19 (d, J=1.5, 1H), 8.11-8.06 (m, 1H),7.66-7.60 (m, 1H), 7.29-7.23 (m, 1H), 5.35-5.28 (s, 2H), 3.91-3.80 (m,1H), 2.39-2.29 (m, 2H), 2.25-2.15 (m, 2H), 2.12-2.00 (m, 1H), 1.92-1.84(m, 1H).

Example 14

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 4-chloromethylpyridine. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O, 350.15; m/z found, 351.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ9.03-8.76 (m, 2H), 8.33-8.16 (m, 4H), 7.67-7.60 (m, 1H), 7.30-7.25 (m,1H), 5.44 (s, 2H), 3.94-3.85 (m, 1H), 2.42-2.32 (m, 2H), 2.29-2.18 (m,2H), 2.12-2.02 (m, 1H), 1.95-1.85 (m, 1H).

Example 15

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared using analogous conditions described inExample 1 using 4-bromomethylbenzonitrile. MS (ESI): mass calcd. forC₂₂H₁₉FN₄O, 374.15; m/z found, 375.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.32-8.28 (d, J=1.4, 1H), 8.23 (s, 1H), 7.79-7.75 (m, 2H), 7.69-7.64 (m,2H), 7.64-7.58 (m, 1H), 7.24-7.20 (m, 1H), 5.12 (s, 2H), 3.84-3.73 (m,1H), 2.32-2.23 (m, 2H), 2.20-2.09 (m, 2H), 2.08-1.96 (m, 1H), 1.89-1.80(m, 1H).

Example 16

3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared using analogous conditions described inExample 1 using 3-bromomethylbenzonitrile. MS (ESI): mass calcd. forC₂₂H₁₉FN₄O, 374.15; m/z found, 375.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.47-8.42 (dd, J=2.3, 1.5, 1H), 8.10-8.06 (d, J=1.5, 1H), 7.80-7.75 (m,1H), 7.73-7.67 (m, 1H), 7.65-7.60 (m, 1H), 7.59-7.53 (dd, J=8.2, 7.4,1H), 7.52-7.47 (m, 1H), 7.18-7.13 (m, 1H), 5.05 (s, 2H), 4.64 (s, 2H),3.81-3.67 (m, 1H), 2.34-2.22 (m, 2H), 2.19-2.06 (m, 2H), 2.06-1.94 (m,1H), 1.92-1.78 (m, 1H).

Example 17

3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide

The title compound was obtained as a side product in the formation of3-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,Example 16. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂, 392.16; m/z found,393.2 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.28-8.22 (dd, J=5.9, 1.5, 2H),8.03-7.98 (m, 1H), 7.90-7.83 (m, 1H), 7.69-7.64 (m, 1H), 7.61-7.55 (m,1H), 7.53-7.47 (m, 1H), 7.24-7.19 (dd, J=7.4, 1.0, 1H), 5.13 (s, 2H),3.86-3.75 (m, 1H), 2.33-2.21 (m, 2H), 2.19-2.08 (m, 2H), 2.08-1.96 (m,1H), 1.91-1.79 (m, 1H).

Example 18

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared using analogous conditions described inExample 1 using 2-bromomethylbenzonitrile. MS (ESI): mass calcd. forC₂₂H₁₉FN₄O, 374.15; m/z found, 375.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.35-8.28 (dd, J=2.5, 1.4, 1H), 8.03-7.97 (d, J=1.5, 1H), 7.95-7.89 (m,1H), 7.83-7.72 (m, 2H), 7.64-7.52 (m, 2H), 7.25-7.18 (d, J=8.3, 1H),6.68 (s, 2H), 5.20 (s, 2H), 3.77-3.65 (m, 1H), 2.25-2.12 (m, 2H),2.12-2.01 (m, 2H), 1.96-1.85 (m, 1H), 1.83-1.70 (m, 1H).

Example 19

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide

The title compound was obtained as a side product in the formation of2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile,Example 18. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₂, 392.16; m/z found,393.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.27 (s, 1H), 8.22-8.16 (d,J=1.5, 1H), 7.77-7.72 (dd, J=7.8, 1.2, 1H), 7.63-7.59 (dd, J=7.6, 1.3,1H), 7.59-7.52 (m, 2H), 7.46-7.41 (m, 1H), 7.26-7.21 (d, J=8.2, 1H),5.30 (s, 2H), 3.89-3.77 (p, J=8.8, 1H), 2.35-2.23 (m, 2H), 2.20-2.09 (m,2H), 2.07-1.96 (m, 1H), 1.89-1.78 (m, 1H).

Example 20

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

To a 20 mL vial were added a stir bar,4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile(82 mg, 0.22 mmol), NaN₃ (576 mg, 8.85 mmol), NH₄Cl (557 mg, 10.4 mmol)and dry DMF (2.0 mL). The resultant mixture was heated at 125° Celsiusfor 21.5 hours before cooling to rt. The mixture was then passed througha syringe filter and the filtrate subjected to HPLC purification to givethe title compound as a yellow solid (47 mg, 40%). MS (ESI): mass calcd.for C₂₂H₂₀FN₇O, 417.17; m/z found, 418.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.35-8.29 (m, 1H), 8.12-8.06 (m, 2H), 8.04-7.97 (d, J=1.5,1H), 7.77-7.69 (d, J=7.9, 2H), 7.60-7.51 (m, 1H), 7.24-7.19 (d, J=8.3,1H), 5.13 (s, 2H), 3.84-3.71 (m, 1H), 2.28-2.18 (m, 2H), 2.17-2.03 (m,2H), 2.02-1.90 (m, 1H), 1.84-1.74 (m, 1H).

Example 21

5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 20 starting from3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile.MS (ESI): mass calcd. for C₂₂H₂₀FN₇O, 417.17; m/z found, 418.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.35-8.30 (m, 1H), 8.24-8.19 (m, 1H),8.08-8.01 (m, 2H), 7.73-7.63 (m, 2H), 7.60-7.52 (m, 1H), 7.26-7.19 (d,J=8.2, 1H), 5.13 (s, 2H), 3.83-3.72 (m, 1H), 2.29-2.18 (m, 2H),2.15-2.04 (m, 2H), 2.00-1.87 (m, 1H), 1.84-1.73 (m, 1H).

Example 22

5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 20 starting from2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-benzonitrile.MS (ESI): mass calcd. for C₂₂H₂₀FN₇O, 417.17; m/z found, 418.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.28-8.23 (m, 1H), 8.01-7.97 (d, J=1.5, 1H),7.90-7.85 (d, J=7.7, 1H), 7.82 (s, 1H), 7.73-7.66 (m, 1H), 7.64-7.57 (d,J=7.7, 1H), 7.55-7.49 (m, 1H), 7.21-7.14 (d, J=8.3, 1H), 6.66 (s, 2H),5.37 (s, 2H), 3.57-3.46 (m, 1H), 2.15-2.04 (m, 2H), 2.04-1.94 (m, 2H),1.93-1.82 (m, 1H), 1.79-1.68 (m, 1H).

Example 23

(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)aceticAcid

The title compound was prepared using analogous conditions described inExample 1 using 2-(4-(bromomethyl)phenyl)acetic acid. MS (ESI): masscalcd. for C₂₃H₂₂FN₃O₃, 407.16; m/z found, 408.1 [M+H]⁺. ¹H NMR (600MHz, CD₃OD) δ 8.31-8.15 (m, 2H), 7.60 (s, 1H), 7.54-7.47 (m, 1H),7.44-7.37 (d, J=7.9, 2H), 7.33-7.29 (d, J=7.8, 2H), 7.19-7.14 (d, J=8.2,1H), 5.01 (s, 2H), 3.81-3.68 (m, 1H), 3.61 (s, 2H), 2.32-2.20 (m, 2H),2.18-2.05 (m, 2H), 2.04-1.94 (m, 1H), 1.88-1.77 (m, 1H).

Example 24

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 1 using 2-chloromethylpyridine. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O, 350.15; m/z found, 351.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.57-8.52 (m, 1H), 8.32-8.28 (dd, J=2.3, 1.5, 1H), 8.06-8.02 (d, J=1.5,1H), 7.95-7.90 (m, 1H), 7.74-7.69 (m, 1H), 7.55-7.50 (m, 1H), 7.44-7.37(m, 1H), 7.24-7.18 (m, 1H), 5.16 (s, 2H), 3.86-3.75 (m, 1H), 2.32-2.22(m, 2H), 2.20-2.08 (m, 2H), 2.07-1.94 (m, 1H), 1.89-1.79 (m, 1H).

Example 25

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N,N-dimethylbenzenesulfonamide

The title compound was prepared using analogous conditions described inExample 1 using 4-(bromomethyl)-N,N-dimethylbenzenesulfonamide. MS(ESI): mass calcd. for C₂₃H₂₅FN₄O₃S, 456.16; m/z found, 457.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.50-8.44 (d, J=1.4, 1H), 8.19-8.11 (m, 1H),7.83-7.74 (m, 2H), 7.69-7.58 (m, 3H), 7.19-7.13 (d, J=8.3, 1H), 5.06 (s,2H), 3.82-3.67 (m, 1H), 2.74 (s, 6H), 2.35-2.19 (m, 2H), 2.19-2.05 (m,2H), 2.05-1.92 (m, 2H), 1.89-1.77 (m, 1H).

Example 26

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzenesulfonamide

The title compound was prepared using analogous conditions described inExample 1 using 4-(bromomethyl)benzenesulfonamide. MS (ESI): mass calcd.for C₂₁H₂₁FN₄O₃S, 428.13; m/z found, 429.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.33-8.30 (dd, J=2.4, 1.4, 1H), 8.02-7.99 (d, J=1.5, 1H),7.90-7.84 (m, 2H), 7.70-7.64 (m, 2H), 7.58-7.52 (m, 1H), 7.39 (s, 2H),7.25-7.19 (d, J=8.3, 1H), 5.11 (s, 2H), 3.79-3.63 (m, 1H), 2.28-2.16 (m,2H), 2.16-2.03 (m, 2H), 2.02-1.88 (m, 1H), 1.84-1.74 (m, 1H).

Example 27

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N-methylbenzenesulfonamide

The title compound was prepared using analogous conditions described inExample 1 using 4-(bromomethyl)-N-methylbenzenesulfonamide. MS (ESI):mass calcd. for C₂₂H₂₃FN₄O₃S, 442.15; m/z found, 443.2 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.34-8.29 (dd, J=2.3, 1.4, 1H), 8.05-7.99 (d,J=1.4, 1H), 7.86-7.79 (m, 2H), 7.73-7.67 (m, 2H), 7.60-7.53 (m, 1H),7.51-7.44 (m, 1H), 7.25-7.19 (d, J=8.2, 1H), 5.12 (s, 2H), 3.79-3.67 (m,1H), 2.46-2.37 (d, J=5.0, 3H), 2.27-2.15 (m, 2H), 2.15-2.02 (m, 2H),2.02-1.88 (m, 1H), 1.84-1.72 (m, 1H).

Example 28

5-{4-Cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

To a solution of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50mg, 0.19 mmol) and 1-(bromomethyl)-4-fluorobenzene (36 μL, 0.29 mmol) inDMSO (1 mL) was added 1 pellet (˜125 mg) of potassium hydroxide. Thereaction was stirred for 16 hours at room temperature before filteringand purifying by HPLC to give5-{4-cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine(37 mg, 39%). MS (ESI): mass calcd. for C₂₁H₁₉F₂N₃O, 367.15; m/z found,368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) 8.30 (d, J=1.3, 1H), 8.22 (s, 1H),7.58 (m, 1H), 7.50-7.43 (m, 2H), 7.20 (d, J=8.0, 1H), 7.15-7.07 (m, 2H),5.01 (s, 2H), 3.83-3.68 (m, 1H), 2.31-2.21 (m, 2H), 2.18-1.93 (m, 3H),1.87-1.78 (m, 1H).

Example 29

5-{4-Cyclobutyl-2-fluoro-3-[(3-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-3-fluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉F₂N₃O,367.15; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (d,J=4.5, 2H), 7.58 (m, 1H), 7.43-7.37 (m, 1H), 7.29-7.19 (m, 3H),7.11-7.04 (m, 1H), 5.05 (d, J=9.9, 2H), 3.86-3.73 (m, 1H), 2.34-2.21 (m,2H), 2.20-1.95 (m, 3H), 1.91-1.80 (m, 1H).

Example 30

5-{4-Cyclobutyl-2-fluoro-3-[(2-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-2-fluorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉F₂N₃O,367.15; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.32 (d,J=1.2, 1H), 8.22 (s, 1H), 7.59 (m, 1H), 7.53-7.48 (m, 1H), 7.42-7.35 (m,1H), 7.24-7.09 (m, 3H), 5.11 (s, 2H), 3.81-3.67 (m, 1H), 2.29-2.17 (m,2H), 2.15-1.91 (m, 3H), 1.88-1.75 (m, 1H).

Example 31

5-{4-Cyclobutyl-3-[(2,6-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-(bromomethyl)-1,3-difluorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈F₃N₃O, 385.14; m/z found, 386.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.24 (s, 1H), 8.18 (d, J=1.4, 1H), 7.59-7.52 (m, 1H), 7.48-7.39 (m, 1H),7.20 (d, J=7.6, 1H), 7.05-6.97 (m, 2H), 5.19 (s, 2H), 3.80-3.66 (m, 1H),2.26-2.15 (m, 2H), 2.13-1.91 (m, 3H), 1.86-1.79 (m, 1H).

Example 32

5-{4-Cyclobutyl-3-[(2,3-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-2,3-difluorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈F₃N₃O, 385.14; m/z found, 386.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.27 (d, J=1.2, 1H), 8.23 (s, 1H), 7.59 (m, 1H), 7.36-7.13 (m, 4H), 5.15(d, J=1.0, 2H), 3.82-3.69 (m, 1H), 2.29-2.19 (m, 2H), 2.17-1.92 (m, 3H),1.90-1.78 (m, 1H).

Example 33

5-{4-Cyclobutyl-3-[(3,4-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-(bromomethyl)-1,2-difluorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈F₃N₃O, 385.14; m/z found, 386.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.29 (d, J=1.3, 1H), 8.23 (s, 1H), 7.59 (m, 1H), 7.45-7.36 (m, 1H),7.33-7.20 (m, 3H), 5.02 (s, 2H), 3.85-3.72 (m, 1H), 2.34-2.23 (m, 2H),2.21-1.97 (m, 3H), 1.90-1.81 (m, 1H).

Example 34

5-{3-[(2-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-2-chlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉ClFN₃O,383.12; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.23 (m,2H), 7.63-7.56 (m, 2H), 7.47-7.42 (m, 1H), 7.38-7.32 (m, 2H), 7.22 (d,J=7.8, 1H), 5.16 (d, J=3.7, 2H), 3.85-3.72 (m, 1H), 2.29-2.20 (m, 2H),2.18-1.91 (m, 3H), 1.88-1.78 (m, 1H).

Example 35

5-{3-[(3-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-3-chlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉ClFN₃O,383.12; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.25 (s, 2H),7.60-7.54 (m, 1H), 7.49 (s, 1H), 7.39-7.33 (m, 3H), 7.21 (d, J=8.3, 1H),5.04 (s, 2H), 3.84-3.70 (m, 1H), 2.32-2.21 (m, 2H), 2.20-1.94 (m, 3H),1.91-1.79 (m, 1H).

Example 36

5-{3-[(4-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-4-chlorobenzene. MS (ESI): mass calcd. for C₂₁H₁₉ClFN₃O,383.12; m/z found, 384.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.31 (d,J=1.3, 1H), 8.22 (s, 1H), 7.62-7.55 (m, 1H), 7.46-7.36 (m, 4H), 7.20 (d,J=7.9, 1H), 5.00 (d, J=9.7, 2H), 3.82-3.69 (m, 1H), 2.31-2.20 (m, 2H),2.17-1.93 (m, 3H), 1.90-1.78 (m, 1H).

Example 37

5-{4-Cyclobutyl-3-[(2,6-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-(bromomethyl)-1,3-dichlorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.29 (d, J=1.4, 1H), 8.21 (t, J=1.4, 1H), 7.62-7.56 (m, 1H), 7.47-7.41(m, 2H), 7.38-7.31 (m, 1H), 7.22 (d, J=7.7, 1H), 5.42 (s, 2H), 3.84-3.70(m, 1H), 2.19-1.75 (m, 6H).

Example 38

5-{4-Cyclobutyl-3-[(2,5-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-(bromomethyl)-1,4-dichlorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.27-8.21 (m, 2H), 7.66 (d, J=2.5, 1H), 7.59 (m, 1H), 7.47-7.41 (m,1H), 7.39-7.34 (m, 1H), 7.24 (m, 1H), 5.13 (s, 2H), 3.86-3.73 (m, 1H),2.33-2.22 (m, 2H), 2.20-2.09 (m, 2H), 2.07-1.96 (m, 1H), 1.92-1.79 (m,1H).

Example 39

5-{4-Cyclobutyl-3-[(2,3-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-2,3-dichlorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.25 (s, 2H), 7.62-7.52 (m, 3H), 7.35 (m, 1H), 7.23 (d, J=8.3, 1H),5.19 (s, 2H), 3.86-3.73 (m, 1H), 2.29-1.78 (m, 7H).

Example 40

5-{4-Cyclobutyl-3-[2,4-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-2,4-dichlorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈Cl₂FN₃O, 417.08; m/z found, 418.0 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.27 (d, J=1.3, 1H), 8.24 (s, 1H), 7.63-7.57 (m, 2H), 7.53 (d, J=2.1,1H), 7.41-7.37 (m, 1H), 7.23 (d, J=7.9, 1H), 5.14 (s, 2H), 3.84-3.72 (m,1H), 2.30-2.20 (m, 2H), 2.18-1.95 (m, 3H), 1.89-1.79 (m, 1H).

Example 41

5-{4-Cyclobutyl-3-[(3,4-dimethylbenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-(bromomethyl)-1,2-dimethylbenzene. MS (ESI): mass calcd. forC₂₃H₂₄FN₃O, 377.19; m/z found, 378.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.29-8.21 (m, 2H), 7.60-7.53 (m, 1H), 7.23-7.02 (m, 4H), 5.02 (d,J=43.3, 2H), 3.82-3.67 (m, 1H), 2.38 (s, 1H), 2.33 (s, 1H), 2.29-2.16(m, 6H), 2.15-1.92 (m, 3H), 1.89-1.78 (m, 1H).

Example 42

5-(3-{[2-Chloro-3-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene. MS (ESI): masscalcd. for C₂₂H₁₈ClF₄N₃O, 451.11; m/z found, 452.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.30-8.22 (m, 2H), 7.91 (d, J=7.7, 1H), 7.83-7.77 (m, 1H),7.64-7.52 (m, 2H), 7.24 (d, J=7.9, 1H), 5.23 (d, J=6.5, 2H), 3.84-3.72(m, 1H), 2.30-2.18 (m, 2H), 2.17-2.07 (m, 2H), 2.07-1.93 (m, 1H),1.88-1.79 (m, 1H).

Example 43

5-(3-{[5-Chloro-2-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-(bromomethyl)-4-chloro-1-(trifluoromethyl)benzene. MS (ESI): masscalcd. for C₂₂H₁₈ClF₄N₃O, 451.11; m/z found, 452.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.25 (s, 2H), 7.92 (s, 1H), 7.75 (d, J=8.5, 1H), 7.66-7.60(m, 1H), 7.57 (d, J=8.4, 1H), 7.27 (d, J=7.9, 1H), 5.21 (s, 2H),3.85-3.73 (m, 1H), 2.33-2.23 (m, 2H), 2.20-2.11 (m, 2H), 2.07-1.96 (m,1H), 1.91-1.82 (m, 1H).

Example 44

5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene. MS (ESI): masscalcd. for C₂₂H₁₈F₅N₃O, 435.14; m/z found, 436.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.26 (d, J=1.3, 1H), 8.23 (s, 1H), 7.92-7.86 (m, 1H), 7.61(m, 1H), 7.55-7.51 (m, 1H), 7.49-7.43 (m, 1H), 7.24 (d, J=8.0, 1H), 5.18(s, 2H), 3.83-3.70 (m, 1H), 2.29-2.19 (m, 2H), 2.18-2.08 (m, 2H),2.06-1.93 (m, 1H), 1.90-1.79 (m, 1H).

Example 45

5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-(bromomethyl)-1-chloro-4-fluorobenzene. MS (ESI): mass calcd. forC₂₁H₁₈ClF₂N₃O, 401.11; m/z found, 402.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD)δ 8.25 (m, 2H), 7.64-7.57 (m, 1H), 7.48-7.40 (m, 2H), 7.23 (d, J=7.9,1H), 7.16-7.08 (m, 1H), 5.13 (s, 2H), 3.87-3.75 (m, 1H), 2.33-2.21 (m,2H), 2.21-1.94 (m, 3H), 1.90-1.80 (m, 1H).

Example 46

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoicAcid

The title compound was prepared in a manner similar to that described inExample 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol andethyl 2-(bromomethyl)benzoate. MS (ESI): mass calcd. for C₂₂H₂₀FN₃O₃,393.15; m/z found, 394.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.30 (d,J=1.0, 1H), 8.22 (s, 1H), 8.06-8.02 (m, 1H), 7.87 (d, J=7.7, 1H),7.66-7.56 (m, 2H), 7.44 (m, 1H), 7.22 (d, J=8.3, 1H), 5.47 (s, 2H),3.87-3.72 (m, 1H), 2.31-2.20 (m, 2H), 2.17-2.07 (m, 2H), 2.05-1.92 (m,1H), 1.87-1.77 (m, 1H).

Example 47

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and3-(bromomethyl)-1-methyl-1H-pyrazole. MS (ESI): mass calcd. forC₁₉H₂₀FN₅O, 353.16; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.30-8.25 (m, 1H), 8.18 (m, 1H), 7.58-7.51 (m, 2H), 7.19 (d, J=8.3, 1H),6.34 (m, 1H), 5.03 (d, J=5.7, 2H), 3.88 (d, J=6.0, 3H), 3.82-3.71 (m,1H), 2.30-2.20 (m, 2H), 2.15-1.95 (m, 3H), 1.89-1.79 (m, 1H).

Example 48

5-{4-Cyclobutyl-3-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methoxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and5-(bromomethyl)-3-cyclopropyl-1,2,4-oxadiazole. MS (ESI): mass calcd.for C₂₀H₂₀FN₅O₂, 381.16; m/z found, 382.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.25 (d, J=1.6, 1H), 8.16 (d, J=1.4, 1H), 7.59 (m, 1H), 7.22(d, J=8.3, 1H), 5.26 (d, J=6.7, 2H), 3.85-3.74 (m, 1H), 2.36-2.25 (m,2H), 2.20-2.01 (m, 4H), 1.92-1.82 (m, 1H), 1.14-1.05 (m, 2H), 1.01-0.95(m, 2H).

Example 49

tert-Butyl [3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate

To a 4 mL vial were added a stir bar,3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (47 mg, 0.18 mmol),tert-butyl bromoacetate (35 μL, 0.24 mmol), powdered KOH (19 mg, 0.34mmol) and DMSO (1.0 mL). The resultant mixture was stirred at roomtemperature for 19 hours before passing it through a syringe filter andsubjecting the filtrate to HPLC purification to give both the titlecompound (20 mg, 22%) and recovered3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (20 mg, 26%). MS(ESI): mass calcd. for C₂₀H₂₄FN₃O₃, 373.18; m/z found, 374.1 [M+H]⁺. ¹HNMR (600 MHz, CDCl₃) δ 8.44-8.38 (d, J=1.4, 1H), 8.21-8.16 (d, J=1.4,1H), 7.64-7.57 (m, 1H), 7.17-7.10 (m, 1H), 4.57-4.49 (d, J=1.3, 2H),3.99-3.88 (m, 1H), 2.41-2.30 (m, 2H), 2.18-1.99 (m, 3H), 1.91-1.79 (m,1H), 1.50 (s, 9H).

Example 50

[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetic acid

To a 20 mL vial containing tert-butyl[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetate (17 mg,0.034 mmol) were added a stir bar and formic acid (1 mL). The reactionmixture was stirred for 20 hours at room temperature and thenconcentrated to dryness to give the title compound (12 mg, 95%). MS(ESI): mass calcd. for C₁₆H₁₆FN₃O₃, 317.12; m/z found, 318.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.25 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H),7.55-7.49 (m, 1H), 7.22-7.16 (d, J=8.2, 1H), 4.65 (s, 2H), 4.04-3.86 (p,J=8.7, 1H), 2.42-2.31 (m, 2H), 2.25-2.12 (m, 2H), 2.12-2.00 (m, 1H),1.94-1.80 (m, 1H).

Example 51

racemic1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridin-2(1H)-one

To a 5 mL reaction tube equipped with reflux condenser and undernitrogen, were added5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine(100 mg, 0.317 mmol), Cs₂CO₃ (103 mg, 0.317 mmol), pyridin-2(1H)-one(151 mg, 1.59 mmol) and DMF (2 mL) to give a yellow suspension. Theresulting mixture was heated at 80° Celsius for 3 hours. The mixture wasthen concentrated to dryness, and the residue purified by HPLC to affordthe title compound (110 mg, 85%). MS (ESI): mass calcd. for C₂₂H₂₃FN₄O₃,410.18; m/z found, 411.1 [M+H]+; ¹H NMR (400 MHz, DMSO-d₆): δ 8.29 (dd,J=2.4, 1.5, 1H), 8.00 (m, 1H), 7.66-7.60 (m, 1H), 7.52 (m, 1H),7.46-7.39 (m, 1H), 7.21 (d, J=8.2, 1H), 6.65 (s, 2H), 6.40 (dd, J=9.1,0.8, 1H), 6.21 (m, 1H), 5.40 (d, J=5.8, 1H), 4.35 (dd, J=13.0, 3.8, 1H),4.18-4.08 (m, 1H), 3.93 (d, J=5.1, 2H), 3.85 (dd, J=17.8, 8.9, 1H), 3.74(dd, J=13.0, 8.4, 1H), 2.30 (m, 2H), 2.13-2.04 (m, 2H), 2.03-1.94 (m,1H), 1.88-1.78 (m, 1H).

Example 52

racemic3-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrimidin-4(3H)-one

The title compound was prepared using analogous conditions described inExample 51 using pyrimidin-4(3H)-one. MS (ESI): mass calcd. forC₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.36 (s, 1H), 8.31-8.27 (m, 1H), 8.00 (d, J=1.5, 1H), 7.92 (d, J=6.6,1H), 7.52 (m, 1H), 7.22 (d, J=8.2, 1H), 6.65 (s, 2H), 6.43 (dd, J=6.6,0.7, 1H), 5.53 (s, 1H), 4.37 (dd, J=13.2, 3.3, 1H), 4.11 (dd, J=8.7,3.5, 1H), 3.96 (d, J=5.3, 2H), 3.90-3.82 (m, 1H), 3.80-3.74 (m, 1H),2.32 (m, 2H), 2.10 (m, 2H), 2.04-1.92 (m, 1H), 1.86-1.77 (m, 1H).

Example 53

racemic2-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridazin-3(2H)-one

The title compound was prepared using analogous conditions described inExample 51 using pyridazin-3(2H)-one. MS (ESI): mass calcd. forC₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.30-8.25 (m, 1H), 7.99 (d, J=1.5, 1H), 7.93 (dd, J=3.8, 1.7, 1H),7.50 (m, 1H), 7.41 (dd, J=9.4, 3.8, 1H), 7.20 (d, J=8.2, 1H), 6.95 (dd,J=9.4, 1.6, 1H), 6.64 (s, 2H), 5.31 (d, J=5.7, 1H), 4.30 (m, 1H), 4.22(d, J=6.6, 2H), 3.98-3.91 (m, 2H), 3.90-3.79 (m, 1H), 2.28 (dd, J=14.3,7.8, 2H), 2.08 (dd, J=19.5, 9.4, 2H), 2.03-1.95 (m, 1H), 1.86-1.75 (m,1H).

Example 54

racemic1-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrazin-2(1H)-one

The title compound was prepared using analogous conditions described inExample 51 using pyrazin-2(1H)-one. MS (ESI): mass calcd. forC₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.35 (d, J=1.5, 1H), 8.07 (dd, J=9.7, 1.3, 2H), 7.66 (dd, J=4.3, 1.1,1H), 7.58 (m, 1H), 7.39 (d, J=4.3, 1H), 7.28 (d, J=8.2, 1H), 6.70 (s,2H), 5.54 (s, 1H), 4.41 (dd, J=12.9, 3.4, 1H), 4.22 (s, 1H), 4.02 (d,J=5.2, 2H), 3.91 (dd, J=17.8, 8.8, 1H), 3.82 (dd, J=12.9, 9.0, 1H),2.41-2.33 (m, 2H), 2.15 (dd, J=19.1, 9.5, 2H), 2.06 (dd, J=18.7, 9.0,1H), 1.94-1.83 (m, 1H).

Example 55

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-5-ylamino)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 using 5-aminopyrimidine. MS (ESI): mass calcd. forC₂₁H₂₃FN₆O₂, 410.19; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.35 (s, 1H), 8.26-8.21 (m, 1H), 8.17 (s, 2H), 7.95 (d, J=1.4, 1H),7.47 (m, 1H), 7.17 (d, J=8.2, 1H), 6.60 (s, 2H), 6.11 (t, J=6.0, 1H),5.26 (s, 1H), 4.03-3.91 (m, 3H), 3.85-3.74 (m, 1H), 3.24-3.11 (m, 2H),2.28-2.16 (m, 2H), 2.10-1.98 (m, 2H), 1.93-1.81 (m, 1H), 1.80-1.69 (m,1H).

Example 56

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-2-ylamino)propan-2-ol

Step A:1-Amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol.

A mixture of5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine(500 mg, 1.59 mmol) and 6 N NH₃ in MeOH (5 mL) was stirred in a sealedtube at 60° Celsius for approximately 8 hours before cooling to rt andconcentrating to dryness to give1-amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol(510 mg, 96%).

Step B

To a 25 mL round-bottomed flask were added a stir bar,1-amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol(150 mg, 0.45 mmol), 2-chloropyrimidine (62 mg, 0.54 mmol), Cs₂CO₃ (440mg, 1.35 mmol) and DMF (6 mL). The mixture was stirred at 60 Celsius forapproximately 24 hours and then diluted with water (20 mL). The aqueousmixture was extracted with EtOAc (3×30 mL) and the combined extractsdried over Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by HPLC to afford the title compound (25 mg, 55%). MS (ESI):mass calcd. for C₂₁H₂₃FN₆O₂, 410.19; m/z found, 411.1 [M+H]⁺. ¹HNMR (400MHz, DMSO-d₆) δ 8.33-8.18 (m, 3H), 7.95 (d, J=1.4, 1H), 7.45 (m, 1H),7.15 (d, J=8.2, 1H), 6.98 (m, 1H), 6.61 (s, 2H), 6.54 (m, 1H), 5.19 (d,J=5.3, 1H), 4.03-3.96 (m, 1H), 3.94-3.85 (m, 2H), 3.83-3.75 (m, 1H),3.49-3.42 (m, 2H), 2.26-2.17 (m, 2H), 2.09-1.97 (m, 2H), 1.93-1.84 (m,1H), 1.80-1.71 (m, 1H).

Example 57

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrazin-2-ylamino)propan-2-ol

The title compound was prepared using analogous conditions described inExample 56 using 2-chloropyrazine. MS (ESI): mass calcd. forC₂₁H₂₃FN₆O₂, 410.19; m/z found, 411.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.23 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H),7.22-6.96 (m, 2H), 6.60 (s, 2H), 5.23 (s, 1H), 3.98 (s, 2H), 3.91 (s,2H), 3.79 (s, 2H), 2.21 (s, 2H), 2.03 (s, 2H), 1.86 (d, J=8.5, 1H), 1.76(s, 1H).

Example 58

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((5-aminopyrimidin-2-yl)amino)propan-2-ol

The title compound was prepared using analogous conditions described inExample 56 using 2-chloro-5-aminopyrimidine. ¹H NMR (400 MHz, DMSO-d₆) δ9.09 (s, 1H), 8.31-8.25 (m, 1H), 8.00 (d, J=1.5, 1H), 7.94 (s, 2H), 7.49(m, 1H), 7.19 (d, J=8.3, 1H), 6.64 (s, 2H), 6.38 (m, 1H), 5.18 (d,J=5.2, 1H), 4.04-3.80 (m, 4H), 3.44 (m, 2H), 2.32-2.21 (m, 2H), 2.06 (m,2H), 1.92 (m, 1H), 1.80 (m, 1H).

Example 59

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((6-aminopyrimidin-4-yl)amino)propan-2-ol

The title compound was prepared using analogous conditions described inExample 56 using 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. forC₂₁H₂₄FN₇O₂, 425.20; m/z found, 426.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.25 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.47 (m, 1H), 7.18 (d,J=8.3, 1H), 6.61 (s, 2H), 6.54 (s, 1H), 6.02 (s, 2H), 5.43 (s, 1H), 5.34(s, 1H), 3.98-3.78 (m, 6H), 2.24 (s, 2H), 2.10-2.01 (m, 2H), 1.92 (dd,J=18.5, 9.0, 1H), 1.77 (d, J=9.1, 1H).

Example 60

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-pyrazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 using pyrazole. MS (ESI): mass calcd. for C₂₀H₂₂FN₅O₂,383.18; m/z found, 384.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1H),8.01 (s, 1H), 7.54-7.42 (m, 3H), 7.08 (d, J=8.2, 1H), 6.23 (d, J=1.9,1H), 4.64 (s, 2H), 4.43 (dd, J=16.1, 5.7, 1H), 4.32 (m, 2H), 3.89 (dd,J=9.6, 4.8, 1H), 3.83 (dd, J=9.6, 5.5, 1H), 3.73 (dd, J=17.6, 8.5, 1H),2.31-2.22 (m, 2H), 2.07 (dd, J=18.7, 9.2, 2H), 2.02-1.93 (m, 1H),1.84-1.77 (m, 1H).

Example 61

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-imidazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 using imidazole. MS (ESI): mass calcd. for C₂₀H₂₂FN₅O₂,383.18; m/z found, 384.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.32 (s, 1H),7.99 (s, 1H), 7.48 (m, 1H), 7.09 (d, J=8.3, 1H), 6.11 (s, 2H), 4.83 (s,1H), 4.32-4.08 (m, 3H), 3.92 (d, J=12.2, 2H), 3.71 (m, 1H), 2.31-2.21(m, 2H), 2.14-2.03 (m, 2H), 2.02-1.93 (m, 1H), 1.81 (dd, J=19.5, 8.6,1H).

Example 62

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 using 1,2,4-triazole. MS (ESI): mass calcd. for C₁₉H₂₁FN₆O₂,384.17; m/z found, 385.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.36 (s, 1H),8.16 (s, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 7.50 (m, 1H), 7.09 (d, J=8.3,1H), 4.63 (s, 2H), 4.48 (dd, J=16.7, 6.1, 1H), 4.35 (dd, J=14.0, 4.7,2H), 3.93 (d, J=4.2, 2H), 3.70 (dd, J=17.6, 8.7, 1H), 2.28 (m, 2H), 2.09(dd, J=14.4, 5.4, 2H), 2.03-1.95 (m, 1H), 1.82 (dd, J=19.2, 8.7, 1 H).

Example 63

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,3-triazol-1-yl)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 using 1,2,3-triazole. MS (ESI): mass calcd. for C₁₉H₂₁FN₆O₂,384.17; m/z found, 385.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.38-8.32 (m,1H), 8.01 (d, J=1.5, 1H), 7.71 (d, J=0.8, 1H), 7.68 (d, J=3.8, 1H), 7.51(m, 1H), 7.09 (d, J=8.2, 1H), 4.75-4.60 (m, 3H), 4.53 (dd, J=14.1, 7.1,1H), 4.39 (dd, J=13.1, 8.0, 1H), 3.98 (dd, J=9.8, 4.9, 1H), 3.89 (dd,J=9.9, 5.9, 1H), 3.71 (m, 1H), 3.38-3.13 (m, 1H), 2.27 (m, 2H),2.14-2.05 (m, 2H), 2.03-1.94 (m, 1H), 1.81 (m, 1H).

Example 64

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(2H-1,2,3-triazol-2-yl)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 using 1,2,3-triazole. MS (ESI): mass calcd. for C₁₉H₂₁FN₆O₂,384.17; m/z found, 385.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.39-8.35 (m,1H), 8.01 (d, J=1.5, 1H), 7.60 (d, J=1.7, 2H), 7.52-7.46 (m, 1H), 7.08(d, J=8.3, 1H), 4.76 (dd, J=13.9, 4.0, 1H), 4.67 (d, J=7.2, 1H), 4.64(d, J=7.2, 2H), 4.49-4.42 (m, 1H), 4.03-3.92 (m, 2H), 3.75 (m, 1H),3.53-3.35 (m, 1H), 2.32-2.22 (m, 2H), 2.12-2.04 (m, 2H), 1.98 (m, 1H),1.85-1.75 (m, 1H).

Example 65

racemic5-Amino-1-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-1H-pyrazole-4-carbonitrile

The title compound was prepared using analogous conditions described inExample 51 using 3-amino-4-cyanopyrazole. MS (ESI): mass calcd. forC₂₁H₂₂FN₇O₂, 423.18; m/z found, 424.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.24 (s, 1H), 7.95 (s, 1H), 7.59-7.34 (m, 2H), 7.17 (d, J=8.0, 1H),6.61 (s, 2H), 6.44 (s, 2H), 5.44 (s, 1H), 4.22-4.11 (m, 1H), 4.07-3.96(m, 2H), 3.92-3.86 (m, 2H), 3.84-3.76 (m, 1H), 2.29-2.20 (m, 2H),2.08-1.93 (m, 3H), 1.82-1.73 (m, 1H).

Example 66

racemic1-(5-Amino-1H-1,2,3-triazol-1-yl)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol

Step A: 1H-1,2,3-Triazol-5-amine

To a 25 mL round-bottomed flask were added a stir bar,5-nitro-1H-1,2,3-triazole (300 mg, 2.63 mmol), Raney-Ni (30 mg), andMeOH (5 mL). The flask was subjected to 1 atm of H₂ and stirred at roomtemperature for approximately 3 hours. The mixture was then filtered,and the filtrate was concentrated to dryness to give1H-1,2,3-triazol-5-amine (181 mg, yield: 82%).

Step B

The title compound was prepared using analogous conditions described inExample 51 using 1H-1,2,3-triazol-5-amine. MS (ESI): mass calcd. forC₁₉H₂₂FN₇O₂, 399.18; m/z found, 400.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.25 (s, 1H), 7.98 (s, 1H), 7.53-7.42 (m, 1H), 7.18 (d, J=8.5, 1H),6.86 (s, 1H), 6.63 (s, 2H), 5.35 (d, J=4.8, 1H), 4.95 (s, 2H), 4.33-4.16(m, 3H), 3.89 (s, 2H), 3.85-3.79 (m, 1H), 2.32-2.21 (m, 2H), 2.12-1.92(m, 3H), 1.82-1.73 (m, 1H).

Example 67

racemic1-((1H-Pyrazol-5-yl)amino)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol

A mixture of5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine(200 mg, 0.63 mmol), 3-aminopyrazole (79 mg, 0.95 mmol), Yb(OTf)₃ (80mg, 0.13 mmol) and DMF (1 mL) was stirred at 100 Celsius forapproximately 24 hours. The mixture was concentrated to dryness and theresidue purified by HPLC to give the title compound (15%, 37 mg). MS(ESI): mass calcd. for C₂₀H₂₃FN₆O₂, 398.19; m/z found, 399.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d); 8.25 (s, 1H), 7.97 (d, J=1.4, 1H), 7.50-7.42 (m,1H), 7.30 (d, J=1.9, 1H), 7.17 (d, J=8.3, 1H), 6.63 (s, 2H), 5.45 (d,J=2.1, 1H), 5.21 (s, 1H), 5.04 (s, 1H), 4.04-3.73 (m, 5H), 3.13-3.05 (m,1H), 2.28-2.21 (m, 2H), 2.10-1.98 (m, 2H), 1.97-1.87 (m, 1H), 1.82-1.72(m, 1H).

Example 68

5-(4-Cyclobutyl-2-fluoro-3-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}phenyl)pyrazin-2-amine

Step A

tert-Butyl4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}piperidine-1-carboxylate(50 mg, 0.11 mmol) was dissolved in formic acid (1 mL) and treated with2 eq. of 6 N HCl (aq). The mixture was allowed to stir for 2 hours andthen concentrated to give the bis-HCl salt. The crude product wastriturated with acetonitrile and then purified by HPLC to give5-(4-cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl)pyrazin-2-amine(46 mg, 98%).

Step B

5-(4-Cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl)pyrazin-2-aminewas dissolved in pyridine (0.32 mL) and treated with a solution ofmethanesulfonyl chloride (10 mg, 0.11 mmol) in DCM (0.25 mL). Thereaction was stirred at room temperature for 18 hours beforeconcentrating to dryness. The crude product was purified by FCC toafford the title compound (6 mg, 10%). MS (ESI): mass calcd. forC₂₁H₂₇FN₄O₃S, 434.18; m/z found, 435.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.38 (m, 1H), 8.20 (d, J=1.4, 1H), 7.60-7.53 (m, 1H), 7.16 (d, J=8.2,1H), 3.89 (t, J=7.8, 3H), 3.84-3.72 (m, 1H), 2.81 (s, 3H), 2.75 (m, 2H),2.40-2.28 (m, 2H), 2.23-1.84 (m, 8H), 1.62-1.48 (m, 2H).

Example 69

5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

A suspension of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (25mg, 0.096 mmol), 2-chloro-4-methylpyrimidine (14 mg, 0.11 mmol), andK₂CO₃ (27 mg, 0.19 mmol) in DMSO (2 mL) was heated at 100° Celsius for16 hours. The reaction was then cooled to room temperature, filtered,and the filtrate directly subjected to HPLC purification to give5-{4-cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine(15 mg, 45%). MS (ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found,352.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.37-8.33 (m, 1H), 8.26 (d,J=1.9, 2H), 7.81-7.75 (m, 1H), 7.26 (d, J=8.3, 1H), 7.00-6.97 (m, 1H),3.75-3.63 (m, 1H), 2.52 (d, J=2.0, 3H), 2.27-2.09 (m, 4H), 2.04-1.92 (m,1H), 1.87-1.76 (m, 1H).

Example 70

5-{4-Cyclobutyl-2-fluoro-3-[(5-methyl-1,2,4-oxadiazol-3-yl)methoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole. MS (ESI): mass calcd.for C₁₈H₁₈FN₅O₂, 355.14; m/z found, 356.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.51-8.46 (m, 1H), 8.09 (d, J=1.4, 1H), 7.61 (m, 1H), 7.16 (d,J=8.2, 1H), 5.15 (s, 2H), 4.72 (s, 2H), 3.91-3.79 (m, 1H), 2.65 (s, 3H),2.39-2.27 (m, 2H), 2.20-1.96 (m, 3H), 1.92-1.79 (m, 1H).

Example 71

5-[4-Cyclobutyl-3-(cyclohexylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand cyclohexylmethyl bromide. MS (ESI): mass calcd. for C₂₁H₂₆FN₃O,355.21; m/z found, 356.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.46 (s, 1H),8.08 (d, J=1.4, 1H), 7.54-7.48 (m, 1H), 7.14 (d, J=8.2, 1H), 4.66 (s,2H), 3.88-3.77 (m, 3H), 2.35 (m, 2H), 2.21-1.99 (m, 3H), 1.96-1.75 (m,6H), 1.74-1.68 (m, 1H), 1.39-1.05 (m, 5H).

Example 72

5-[4-Cyclobutyl-3-(cyclopropylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand cyclopropylmethyl bromide. MS (ESI): mass calcd. for C₁₈H₂₀FN₃O,313.16; m/z found, 314.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.44 (m,1H), 8.08 (d, J=1.5, 1H), 7.56-7.49 (m, 1H), 7.15 (d, J=8.3, 1H), 4.65(s, 2H), 3.95-3.83 (m, 3H), 2.42-2.32 (m, 2H), 2.23-1.98 (m, 3H),1.93-1.81 (m, 1H), 1.34-1.23 (m, 1H), 0.65-0.58 (m, 2H), 0.36-0.29 (m,2H).

Example 73

Ethyl5-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylate

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand ethyl 5-(chloromethyl)-2-furancarboxylate. MS (ESI): mass calcd. forC₂₂H₂₂FN₃O₄, 411.16; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.47 (s, 1H), 8.09 (d, J=1.4, 1H), 7.60-7.53 (m, 1H), 7.17-7.11 (m, 2H),6.50 (d, J=3.4, 1H), 5.09 (s, 2H), 4.71 (s, 2H), 4.38 (q, J=7.1, 2H),3.83-3.70 (m, 1H), 2.35-2.25 (m, 2H), 2.16-1.95 (m, 3H), 1.90-1.79 (m,1H), 1.39 (t, J=7.1, 3H).

Example 74

tert-Butyl4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}piperidine-1-carboxylate

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. MS (ESI): masscalcd. for C₂₅H₃₃FN₄O₃, 456.25; m/z found, 457.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.45 (s, 1H), 8.09 (d, J=1.4, 1H), 7.59-7.46 (m, 1H), 7.15(d, J=8.3, 1H), 4.65 (s, 2H), 4.31-4.10 (m, 2H), 3.92-3.73 (m, 3H),2.92-2.63 (m, 2H), 2.42-2.27 (m, 2H), 2.24-1.93 (m, 4H), 1.94-1.80 (m,3H), 1.47 (s, 9H), 1.44-1.21 (m, 2H).

Example 75

5-{4-Cyclobutyl-2-fluoro-3-[(3-methyl-1,2,4-oxadiazol-5-yl)methoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole. MS (ESI): mass calcd.for C₁₈H₁₈FN₅O₂, 355.14; m/z found, 356.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.47 (dd, J=2.4, 1.6, 1H), 8.09 (d, J=1.5, 1H), 7.66-7.58 (m,1H), 7.17 (d, J=8.1, 1H), 5.26 (s, 2H), 4.67 (s, 2H), 3.89-3.77 (m, 1H),2.46 (s, 3H), 2.39-2.29 (m, 2H), 2.21-1.98 (m, 3H), 1.92-1.81 (m, 1H).

Example 76

5-(4-Cyclobutyl-2-fluoro-3-{[2-methoxy-5-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 2-methoxy-5-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd.for C₂₂H₂₁F₆N₃O₂S, 505.13; m/z found, 506.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.50-8.46 (m, 1H), 8.10 (d, J=1.5, 1H), 8.03 (d, J=2.8, 1H),7.72 (dd, J=9.0, 2.8, 1H), 7.61-7.54 (m, 1H), 7.16 (d, J=8.2, 1H), 6.90(d, J=9.0, 1H), 5.11 (s, 2H), 4.65 (s, 2H), 3.88 (s, 3H), 3.85-3.73 (m,1H), 2.33-2.23 (m, 2H), 2.20-2.08 (m, 2H), 2.06-1.91 (m, 2H), 1.91-1.78(m, 1H).

Example 77

5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-5-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 2-fluoro-5-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd.for C₂₁H₁₈F₇N₃OS, 493.10 m/z found, 494.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.49-8.46 (m, 1H), 8.13-8.08 (m, 2H), 7.76 (m, 1H), 7.63-7.57(m, 1H), 7.21-7.14 (m, 2H), 5.17 (s, 2H), 4.69 (s, 2H), 3.82-3.72 (m,1H), 2.33-2.24 (m, 2H), 2.21-2.09 (m, 2H), 2.08-1.95 (m, 1H), 1.90-1.80(m, 1H).

Example 78

5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-4-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 2-fluoro-4-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd.for C₂₁H₁₈F₇N₃OS, 493.10; m/z found, 494.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.50-8.45 (m, 1H), 8.10 (d, J=1.5, 1H), 7.79 (m, 1H), 7.66-7.58(m, 2H), 7.53 (dd, J=9.9, 2.1, 1H), 7.18 (d, J=8.2, 1H), 5.15 (s, 2H),4.67 (s, 2H), 3.78 (p, J=8.7, 1H), 2.34-2.25 (m, 2H), 2.21-2.10 (m, 2H),2.09-1.96 (m, 2H), 1.91-1.81 (m, 1H).

Example 79

5-(4-Cyclobutyl-2-fluoro-3-{[4-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 4-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd. forC₂₁H₁₉F₆N₃OS, 475.11 m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.49-8.46 (m, 1H), 8.10 (d, J=1.5, 1H), 7.80 (d, J=8.7, 2H), 7.62-7.55(m, 3H), 7.18 (d, J=8.1, 1H), 5.10 (s, 2H), 4.65 (s, 2H), 3.78 (p,J=8.7, 1H), 2.34-2.25 (m, 2H), 2.22-2.09 (m, 2H), 2.09-1.95 (m, 1H),1.91-1.81 (m, 1H).

Example 80

5-(4-Cyclobutyl-2-fluoro-3-{[3-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 3-(pentafluorosulfur)benzyl bromide. MS (ESI): mass calcd. forC₂₁H₁₉F₆N₃OS, 475.11; m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.48 (dd, J=2.2, 1.6, 1H), 8.10 (d, J=1.5, 1H), 7.91 (s, 1H), 7.74 (d,J=8.2, 1H), 7.59 (dd, J=15.1, 7.3, 2H), 7.50 (m, 1H), 7.17 (d, J=8.1,1H), 5.12 (s, 2H), 4.67 (s, 2H), 3.82-3.71 (m, 1H), 2.33-2.24 (m, 2H),2.21-2.08 (m, 2H), 2.08-1.95 (m, 1H), 1.91-1.80 (m, 1H).

Example 81

5-(4-Cyclobutyl-2-fluoro-3-{[2-(pentafluoro-lambda˜6˜-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 2-(pentafluorousulfur)benzyl bromide. MS (ESI): mass calcd. forC₂₁H₁₉F₆N₃OS, 475.11; m/z found, 476.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.49-8.46 (m, 1H), 8.10 (d, J=1.4, 1H), 7.91 (s, 1H), 7.74 (d, J=8.3,1H), 7.64-7.56 (m, 2H), 7.50 (m, 1H), 7.17 (d, J=8.2, 1H), 5.12 (s, 2H),4.66 (s, 2H), 3.76 (p, J=8.7, 1H), 2.33-2.24 (m, 2H), 2.20-2.08 (m, 2H),2.07-1.94 (m, 1H), 1.91-1.79 (m, 1H).

Example 82

5-[4-Cyclobutyl-3-(cyclobutylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand cyclobutylmethyl bromide. MS (ESI): mass calcd. for C₁₉H₂₂FN₃O,327.17; m/z found, 328.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd,J=2.2, 1.6, 1H), 8.08 (d, J=1.5, 1H), 7.51 (dd, J=13.7, 6.1, 1H), 7.14(d, J=8.0, 1H), 4.70 (s, 2H), 4.00 (dd, J=6.8, 0.9, 2H), 3.88-3.78 (m,1H), 2.86-2.74 (m, 1H), 2.39-2.30 (m, 2H), 2.22-1.81 (m, 11H).

Example 83

5-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-pyrazin-2-amine

5-[3-(Benzyloxy)-4-chloro-2-fluorophenyl]pyrazin-2-amine (59 mg, 0.18mmol), 2-dicyclohexylphosphino-2′, 6′-dimethoxy-1, 1′-biphenyl (6 mg,0.01 mmol) and palladium acetate (2 mg, 0.009 mmol) were added to avial. The vial was capped, evacuated and back-filled with N₂.Cyclobutylzinc bromide (0.5 M solution in THF; 0.54 mL, 0.27 mmol) wasadded and the mixture heated at 65° Celsius for 18 hours. The reactionmixture was concentrated to dryness and the residue subjected to FCC.Further purification by HPLC and prep TLC gave the title compound (6 mg,10%). MS (ESI): mass calcd. for C₂₁H₂₀FN₃O, 349.16; m/z found, 350.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.52-8.47 (m, 1H), 8.10 (d, J=1.5,1H), 7.59-7.53 (m, 1H), 7.51-7.46 (m, 2H), 7.44-7.32 (m, 3H), 7.16 (d,J=8.1, 1H), 5.05 (s, 2H), 4.65 (s, 2H), 3.79 (p, J=8.7, 1H), 2.34-2.23(m, 2H), 2.19-2.07 (m, 2H), 2.06-1.93 (m, 1H), 1.90-1.78 (m, 1H).

Example 84

4-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}benzoicAcid

To a 5 mL vial containing a stir bar,3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol)and 4-(2-bromoethyl)benzoic acid (49 mg, 0.21 mmol) were added KOt-Bu(37 mg, 0.42 mmol) and DMSO (0.5 mL). The resultant mixture was stirredat rt for 15 hours. The mixture was passed through a syringe filter andthe filtrate subjected to HPLC purification to afford the title compound(10 mg, 13%). MS (ESI): mass calcd. for C₂₃H₂₂FN₃O₃, 407.16; m/z found,408.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 8.18 (s, 1H), 8.03(d, J=8.2, 2H), 7.51 (m, 1H), 7.41 (d, J=8.2, 2H), 7.13 (d, J=8.0, 1H),4.26 (t, J=6.6, 2H), 3.61-3.48 (m, 1H), 3.18 (t, J=6.7, 2H), 2.23-2.00(m, 4H), 1.98-1.74 (m, 2H).

Example 85

5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylicAcid

Ethyl5-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylate(48 mg, 0.12 mmol) was dissolved in THF (2 mL) and treated with aqueousLiOH (1.0 N, 0.5 mL). The mixture was stirred at rt for 15 hours. Thereaction mixture was purified using HPLC to afford the title compound.MS (ESI): mass calcd. for C₂₀H₁₈FN₃O₄, 383.13; m/z found, 384.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.22-8.15 (m, 2H), 7.50-7.43 (m, 1H), 7.08 (m,2H), 6.43 (d, J=3.4, 1H), 5.00 (s, 2H), 2.27-2.16 (m, 2H), 2.07-1.89 (m,3H), 1.80-1.70 (m, 1H).

Example 86

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-6-methylpyrimidin-4-amine. MS (ESI): mass calcd. forC₁₉H₁₉FN₆O, 366.16; m/z found, 367.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.29-8.24 (m, 1H), 8.08 (d, J=1.5, 1H), 7.81 (m, 1H), 7.31 (d, J=8.2,1H), 6.32 (d, J=0.9, 1H), 3.73-3.63 (m, 1H), 2.45 (s, 3H), 2.32-2.18 (m,4H), 2.12-2.02 (m, 1H), 1.94-1.82 (m, 1H).

Example 87

5-{4-Cyclobutyl-2-fluoro-3-[(4-phenylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4-phenylpyrimidine. MS (ESI): mass calcd. for C₂₄H₂₀FN₅O,413.17; m/z found, 414.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 8.57 (d, J=5.0,1H), 8.45 (s, 1H), 8.16 (s, 1H), 8.06-8.01 (m, 2H), 7.89 (t, J=7.9, 1H),7.54-7.45 (m, 4H), 7.29 (d, J=8.3, 1H), 3.82-3.70 (m, 1H), 2.28-2.13 (m,4H), 2.03-1.92 (m, 1H), 1.86-1.75 (m, 1H).

Example 88

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4-(methylthio)pyrimidine. MS (ESI): mass calcd. forC₁₉H₁₈FN₅OS, 383.12; m/z found, 384.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.24-8.18 (m, 3H), 7.78 (m, 1H), 7.30 (d, J=8.2, 1H), 7.09 (d, J=5.5,1H), 3.73-3.58 (m, 1H), 2.32 (s, 3H), 2.24-2.13 (m, 4H), 2.04-1.92 (m,1H), 1.87-1.77 (m, 1H).

Example 89

5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4,6-dimethylpyrimidine. MS (ESI): mass calcd. for C₂₀H₂₀FN₅O,365.16; m/z found, 366.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.35 (d,J=1.2, 1H), 8.21 (s, 1H), 7.86-7.78 (m, 1H), 7.25 (d, J=8.4, 1H), 6.80(s, 1H), 3.77-3.65 (m, 1H), 2.41 (s, 6H), 2.27-2.08 (m, 4H), 2.02-1.91(m, 1H), 1.85-1.75 (m, 1H).

Example 90

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4-isopropylpyrimidine. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O,379.18; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.56-8.51 (m,1H), 8.31 (d, J=1.4, 1H), 8.26 (s, 1H), 7.82 (m, 1H), 7.41-7.38 (m, 1H),7.29 (d, J=8.4, 1H), 3.79-3.66 (m, 1H), 3.41-3.38 (m, 1H), 2.26-2.10 (m,4H), 2.07-1.94 (m, 1H), 1.89-1.79 (m, 1H), 1.52 (s, 6H).

Example 91

5-{4-Cyclobutyl-2-fluoro-3-[(4-thiophen-2-ylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4-(thiophen-2-yl)pyrimidine. MS (ESI): mass calcd. forC₂₂H₁₈FN₅OS, 419.12; m/z found, 420.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.47 (d, J=5.3, 1H), 8.42-8.37 (m, 1H), 8.08 (d, J=1.4, 1H), 7.81-7.71(m, 2H), 7.54-7.51 (m, 1H), 7.34 (d, J=3.2, 1H), 7.26 (d, J=8.3, 1H),7.16-7.12 (m, 1H), 3.80-3.66 (m, 1H), 2.29-2.10 (m, 4H), 2.03-1.90 (m,1H), 1.85-1.75 (m, 1H).

Example 92

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carbonitrile

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloropyrimidine-4-carbonitrile. ¹H NMR (400 MHz, CDCl₃) δ 8.76 (d,J=4.9, 5H), 8.71 (d, J=1.5, 5H), 8.47 (d, J=6.0, 4H), 7.97 (s, 4H),7.93-7.82 (m, 11H), 3.74-3.61 (m, 7H), 2.25-2.10 (m, 23H), 2.03-1.91 (m,7H), 1.81 (d, J=8.1, 6H).

Example 93

5-{4-Cyclobutyl-2-fluoro-3-[(4-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂,367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49-8.45 (m,1H), 8.18 (d, J=5.7, 1H), 8.08 (d, J=1.5, 1H), 7.82-7.74 (m, 1H), 7.22(d, J=8.3, 1H), 6.47 (d, J=5.7, 1H), 3.93 (s, 3H), 3.76-3.66 (m, 1H),2.26-2.12 (m, 4H), 2.03-1.91 (m, 1H), 1.86-1.77 (m, 1H).

Example 94

5-{4-Cyclobutyl-2-fluoro-3-[(5-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-5-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂,367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.29-8.20 (m,4H), 7.80-7.73 (m, 1H), 7.25 (d, J=8.2, 1H), 3.90 (s, 3H), 3.75-3.63 (m,1H), 2.27-2.09 (m, 4H), 2.03-1.93 (m, 1H), 1.85-1.76 (m, 1H).

Example 95

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4-(methylsulfonyl)pyrimidine. MS (ESI): mass calcd. forC₁₉H₁₈FN₅O₃S, 415.11; m/z found, 416.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.87 (d, J=4.8, 1H), 8.44 (s, 1H), 8.09 (d, J=1.4, 1H), 7.86-7.81 (m,1H), 7.72 (d, J=4.8, 1H), 7.24 (s, 1H), 4.70 (s, 2H), 3.73-3.63 (m, 1H),3.20 (s, 3H), 2.27-2.08 (m, 4H), 2.03-1.93 (m, 1H), 1.86-1.78 (m, 1H).

Example 96

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine

A suspension of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50mg, 0.19 mmol), 4-chloro-6-methylpyrimidin-2-amine (30 mg, 0.20 mmol),K₂CO₃ (53 mg, 0.39 mmol), and 18-crown-6 (3 mg, 0.01 mmol) in DMSO (2mL) was heated for 16 hours at 140° Celsius. The reaction was thencooled to room temperature, filtered, and the filtrate directlysubjected to HPLC purification to give4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine(12 mg, 16%). MS (ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found,367.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.27-8.22 (m, 1H), 8.11 (d,J=1.5, 1H), 7.78 (m, 1H), 7.29 (d, J=8.3, 1H), 6.67 (d, J=0.8, 1H),3.68-3.55 (m, 1H), 2.51 (d, J=0.7, 3H), 2.31-2.13 (m, 4H), 2.11-1.98 (m,1H), 1.91-1.81 (m, 1H).

Example 97

5-{4-Cyclobutyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂,367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.46 (m,1H), 8.43-8.42 (m, 1H), 8.09-8.08 (m, 1H), 7.82-7.78 (m, 1H), 7.23-7.21(m, 1H), 6.26-6.25 (m, 1H), 4.67 (s, 2H), 4.00 (s, 3H), 3.64-3.57 (m,1H), 2.25-2.11 (m, 4H), 2.01-1.92 (m, 1H), 1.84-1.78 (m, 1H).

Example 98

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol

Title compound was obtained as a side product from the reactiondescribed in Example 96 using3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O₂,353.13; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.30 (m,1H), 8.15-8.13 (m, 1H), 8.00-7.98 (m, 1H), 7.78-7.73 (m, 1H), 7.54-7.52(m, 1H), 7.28-7.24 (m, 1H), 5.73 (s, 1H), 3.67-3.61 (m, 1H), 2.34-2.25(m, 2H), 2.24-2.14 (m, 2H), 2.09-1.99 (m, 1H), 1.91-1.82 (s, 1H).

Example 99

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methoxypyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-chloro-6-methoxypyrimidin-2-amine. MS (ESI): mass calcd. forC₁₉H₁₉FN₆O₂, 382.15; m/z found, 383.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.26-8.21 (m, 2H), 7.81-7.74 (m, 1H), 7.31-7.26 (m, 1H), 5.67 (s, 1H),3.93 (s, 3H), 3.67-3.57 (m, 1H), 2.30-2.13 (m, 4H), 2.08-1.97 (m, 1H),1.89-1.80 (m, 1H).

Example 100

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methoxypyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and6-chloro-2-methoxypyrimidin-4-amine. MS (ESI): mass calcd. forC₁₉H₁₉FN₆O₂, 382.15; m/z found, 383.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.27-8.18 (m, 2H), 7.82 (CDCl₃, 1H), 7.33 (d, J=8.3, 1H), 5.69 (d,J=8.6, 1H), 3.86 (d, J=8.8, 3H), 3.71-3.59 (m, 1H), 2.32-2.15 (m, 4H),2.10-2.00 (m, 1H), 1.87 (t, J=9.0, 1H).

Example 101

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile

To a 5 mL vial containing a stir bar,3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol)and 4-fluorobenzonitrile (26 mg, 0.21 mmol) were added Cs₂CO₃ (96 mg,0.29 mmol) and 0.55 mL DMSO. The resultant mixture was stirred at 80°Celsius for approximately 15 hours. The mixture was cooled to roomtemperature and then passed through a syringe filter. The filtrate wassubjected to FCC to give the title compound (36 mg, 52%). MS (ESI): masscalcd. for C₂₁H₁₇FN₄O, 360.14; m/z found, 361.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.46-8.42 (m, 1H), 8.11-8.08 (d, J=1.5, 1H), 7.85-7.78 (m, 1H),7.63-7.56 (m, 2H), 7.29-7.23 (m, 1H), 6.97-6.90 (m, 2H), 4.77-4.66 (s,2H), 3.63-3.51 (m, 1H), 2.26-2.07 (m, 4H), 2.03-1.89 (m, 1H), 1.87-1.76(m, 1H).

Example 102

5-(4-Cyclobutyl-2-fluor-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 2-fluoro-6-(trifluoromethyl)pyridine. MS(ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.45 (dd, J=2.4, 1.6, 1H), 8.09 (d, J=1.5, 1H),7.84 (dd, J=11.7, 4.0, 1H), 7.81-7.75 (m, 1H), 7.37 (d, J=7.3, 1H), 7.23(d, J=8.1, 1H), 7.12 (d, J=8.4, 1H), 4.65 (s, 2H), 3.64 (p, J=8.8, 1H),2.23-2.07 (m, 4H), 2.00-1.87 (m, 1H), 1.85-1.74 (m, 1H).

Example 103

Methyl 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoate

The title compound was prepared using conditions similar to thosedescribed in Example 101 using methyl 4-fluorobenzoate. MS (ESI): masscalcd. for C₂₂H₂₀FN₃O₃, 393.15; m/z found, 394.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.46 (d, J=1.2, 1H), 8.19 (d, J=1.0, 1H), 8.03-7.96 (m,2H), 7.87 (m, 1H), 7.30 (d, J=8.4, 1H), 6.88 (d, J=8.8, 2H), 3.90 (s,3H), 3.68-3.57 (m, 1H), 2.26-2.06 (m, 4H), 2.02-1.88 (m, 1H), 1.86-1.75(m, 1H)

Example 104

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 2-chloro-5-(trifluoromethyl)-pyrimidine.MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=0.6, 2H), 8.48-8.43 (m, 1H), 8.09(d, J=1.5, 1H), 7.88-7.79 (m, 1H), 7.25 (d, J=8.3, 1H), 4.76 (s, 2H),3.67 (p, J=8.9, 1H), 2.27-2.08 (m, 4H), 2.05-1.90 (m, 1H), 1.88-1.76 (m,1H).

Example 105

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 2-chloro-5-(trifluoromethyl)pyrazine. MS(ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.60 (d, J=0.9, 1H), 8.47-8.43 (m, 1H), 8.41 (d,J=0.4, 1H), 8.09 (d, J=1.5, 1H), 7.84 (m, 1H), 7.25 (d, J=8.7, 1H), 4.71(s, 2H), 3.60 (p, J=8.8, 1H), 2.26-2.08 (m, 4H), 2.05-1.91 (m, 1H),1.89-1.75 (m, 1H).

Example 106

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridazin-3-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 3-chloro-6-trifluoromethyl-pyridazine. MS(ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.46-8.43 (m, 1H), 8.08 (d, J=1.4, 1H), 7.88-7.79(m, 2H), 7.43 (d, J=9.1, 1H), 7.23 (d, J=8.3, 1H), 4.67 (s, 2H),3.68-3.56 (m, 1H), 2.24-2.14 (m, 4H), 2.03-1.89 (m, 1H), 1.87-1.77 (m,1H).

Example 107

Methyl6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylate

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 6-fluoronicotinic acid methyl ester. MS (ESI): mass calcd. forC₂₁H₁₉FN₄O₃, 394.14; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.77 (dd, J=2.3, 0.5, 1H), 8.46 (s, 1H), 8.31 (dd, J=8.6, 2.3, 1H), 8.08(d, J=1.3, 1H), 7.83-7.76 (m, 1H), 7.23 (d, J=8.3, 1H), 7.04 (dd, J=8.6,0.6, 1H), 4.68 (s, 2H), 3.91 (s, 3H), 3.67-3.55 (m, 1H), 2.23-2.07 (m,4H), 2.00-1.87 (m, 1H), 1.85-1.75 (m, 1H).

Example 108

5-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 2-cyano-5-fluoropyridine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O,361.13; m/z found, 362.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d,J=2.8, 1H), 8.45-8.41 (m, 1H), 8.10 (d, J=1.5, 1H), 7.88-7.81 (m, 1H),7.63 (d, J=8.6, 1H), 7.28 (d, J=7.7, 1H), 7.19-7.12 (m, 1H), 4.79 (s,2H), 3.58 (p, J=8.8, 1H), 2.26-2.07 (m, 4H), 2.05-1.91 (m, 1H),1.89-1.78 (m, 1H).

Example 109

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 4-chloro-pyridine-2-carbonitrile. MS(ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.54 (d, J=5.7, 1H), 8.47-8.43 (m, 1H), 8.10 (d,J=1.2, 1H), 7.88 (m, 1H), 7.32-7.25 (m, 1H), 7.22 (d, J=2.3, 1H), 6.99(dd, J=5.7, 2.4, 1H), 4.74 (s, 2H), 3.54 (p, J=8.9, 1H), 2.25-2.08 (m,4H), 2.05-1.92 (m, 1H), 1.89-1.79 (m, 1H).

Example 110

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 3-cyano-2-fluoropyridine. MS (ESI): masscalcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.48-8.44 (m, 1H), 8.29 (dd, J=5.0, 1.9, 1H), 8.09 (d, J=1.5,1H), 8.03 (dd, J=7.6, 1.9, 1H), 7.86-7.78 (m, 1H), 7.23 (d, J=8.3, 1H),7.11 (dd, J=7.6, 5.0, 1H), 4.66 (s, 2H), 3.65 (p, J=8.9, 1H), 2.29-2.11(m, 4H), 2.06-1.92 (m, 1H), 1.87-1.76 (m, 1H).

Example 111

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 2-cyano-6-fluoropyridine. MS (ESI): masscalcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.46 (dd, J=2.2, 1.6, 1H), 8.10 (d, J=1.5, 1H), 7.86-7.76 (m,2H), 7.42 (dd, J=7.3, 0.7, 1H), 7.25-7.19 (m, 2H), 4.69 (s, 2H), 3.59(p, J=8.9, 1H), 2.22-2.09 (m, 4H), 1.99-1.87 (m, 1H), 1.86-1.76 (m, 1H).

Example 112

3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 using 2-cyano-3-fluoropyridine. MS (ESI): masscalcd. for C₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.44 (dd, J=2.2, 1.6, 1H), 8.39 (dd, J=4.5, 1.2, 1H), 8.10 (d,J=1.5, 1H), 7.89-7.80 (m, 1H), 7.39 (dd, J=8.7, 4.5, 1H), 7.28 (d,J=7.2, 1H), 7.02 (m, 1H), 4.78 (s, 2H), 3.69-3.58 (m, 1H), 2.31-2.09 (m,4H), 2.07-1.94 (m, 1H), 1.89-1.78 (m, 1H).

Example 113

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand 2-fluoro-5-(trifluoromethyl)pyridine. MS (ESI): mass calcd. forC₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.46 (s, 1H), 8.40 (s, 1H), 8.08 (d, J=1.4, 1H), 7.93 (dd, J=8.7, 2.3,1H), 7.80 (m, 1H), 7.23 (d, J=8.3, 1H), 7.12 (d, J=8.7, 1H), 4.70 (s,2H), 3.61 (p, J=8.9, 1H), 2.25-2.08 (m, 4H), 2.00-1.89 (m, 1H),1.86-1.75 (m, 1H).

Example 114

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 using acetonitrile with 10% DMF as the solventand using 5-cyano-2-fluoropyridine. MS (ESI): mass calcd. forC₂₀H₁₆FN₅O, 361.13; m/z found, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.47-8.41 (m, 2H), 8.09 (d, J=1.5, 1H), 7.96 (dd, J=8.6, 2.3, 1H),7.84-7.78 (m, 1H), 7.23 (d, J=8.3, 1H), 7.13 (dd, J=8.6, 0.6, 1H), 4.70(s, 2H), 3.58 (p, J=8.9, 1H), 2.23-2.08 (m, 4H), 2.02-1.89 (m, 1H),1.86-1.75 (m, 1H).

Example 115

5-{4-Cyclobutyl-2-fluoro-3-[4-(pentafluoro-lambda˜6˜-sulfanyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 130° Celsius via microwaveirradiation for 1 hour and using 4-fluorophenylsulfur pentafluoride. MS(ESI): mass calcd. for C₂₀H₁₇F₆N₃OS, 461.10; m/z found, 462.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.42 (d, J=1.2, 1H), 8.21 (s, 1H), 7.87 (m, 1H),7.73-7.65 (m, 2H), 7.34-7.27 (m, 1H), 6.89 (d, J=8.9, 2H), 3.90 (s, 2H),3.68-3.56 (m, 1H), 2.30-2.19 (m, 2H), 2.19-2.09 (m, 2H), 2.06-1.92 (m,1H), 1.89-1.75 (m, 1H).

Example 116

5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 130° Celsius via microwaveirradiation for 1 hour and using 4-fluorophenyl methyl sulfone. MS(ESI): mass calcd. for C₂₁H₂₀FN₃O₃S, 413.12; m/z found, 414.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.47 (d, J=1.2, 1H), 8.18 (s, 1H), 7.94-7.84 (m,3H), 7.31 (d, J=8.4, 1H), 7.00 (d, J=8.8, 2H), 3.61 (p, J=8.9, 1H), 3.08(s, 3H), 2.29-2.07 (m, 4H), 2.05-1.91 (m, 1H), 1.88-1.77 (m, 1H).

Example 117

5-{4-Cyclobutyl-2-fluoro-3-[2-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-fluorophenylmethylsulfone. MS (ESI):mass calcd. for C₂₁H₂₀FN₃O₃S, 413.12; m/z found, 414.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.44-8.41 (m, 1H), 8.11-8.06 (m, 2H), 7.87-7.80 (m,1H), 7.46 (m, 1H), 7.33 (d, J=8.3, 1H), 7.18 (m, 1H), 6.64 (d, J=8.4,1H), 4.74 (s, 2H), 3.73 (p, J=8.7, 1H), 3.38 (s, 3H), 2.45-2.33 (m, 1H),2.29-2.16 (m, 1H), 2.12-1.90 (m, 3H), 1.86-1.75 (m, 1H).

Example 118

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-bromopyrimidine. MS (ESI): masscalcd. for C₁₈H₁₆FN₅O, 337.13 m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.57 (d, J=4.8, 2H), 8.49-8.45 (m, 1H), 8.09 (d, J=1.5, 1H),7.83-7.77 (m, 1H), 7.24 (d, J=8.2, 1H), 7.83-7.78 (m, 1H), 4.66 (s, 2H),3.70 (p, J=8.8, 1H), 2.27-2.08 (m, 4H), 2.03-1.89 (m, 1H), 1.85-1.75 (m,1H).

Example 119

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine

Method 1:

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 2 hours and using 4-amino-2-chloropyrimidine.

Method 2:

A mixture of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (17.0g, 65.6 mmol), K₂CO₃ (13.6 g, 98.4 mmol), 2-chloropyrimidin-4-amine (8.9g, 69 mmol), 18-crown-6 (0.87 g, 3.3 mmol), and DMA (131 mL) was stirredat 120° Celsius for 15 hours. Water (306 mL) was added, and the reactionmixture cooled to room temperature. Solid precipitate was collected byvacuum filtration and dried in a vacuum oven at 70° Celsius to give thecrude product (23.1 g, 100%). The solid was recrystallized from EtOH andtreated successively with activated charcoal and silica-supported thiolto remove residual Pd and afford the title compound (13.0 g, 56%). MS(ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.25 (s, 1H), 8.01 (d, J=1.5, 1H), 7.83 (d,J=5.8, 1H), 7.66 (m, 1H), 7.23 (d, J=8.3, 1H), 7.06 (s, 2H), 6.67 (s,2H), 6.17 (d, J=5.8, 1H), 3.60-3.47 (m, 1H), 2.19-2.01 (m, 4H),1.98-1.85 (m, 1H), 1.80-1.68 (m, 1H).

Example 120

5-{3-[3,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation 1 hour and using 3,4-bis-(trifluoromethyl)fluorobenzene. MS(ESI): mass calcd. for C₂₂H₁₆F₇N₃O, 471.12; m/z found, 472.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.45 (dd, J=2.2, 1.6, 1H), 8.09 (d, J=1.5, 1H),7.89-7.82 (m, 1H), 7.74 (d, J=8.8, 1H), 7.42 (d, J=2.5, 1H), 7.29 (d,J=8.3, 1H), 7.00 (dd, J=8.8, 2.1, 1H), 4.76 (s, 2H), 3.59 (p, J=8.8,1H), 2.27-2.07 (m, 4H), 2.05-1.91 (m, 1H), 1.88-1.76 (m, 1H).

Example 121

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-fluoro-3-(trifluoromethyl)pyridine.MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.46 (s, 1H), 8.24 (d, J=3.7, 1H), 8.08 (s,1H), 8.01 (d, J=7.7, 1H), 7.80 (m, 1H), 7.23 (d, J=8.4, 1H), 7.13-7.06(m, 1H), 4.62 (s, 2H), 3.71-3.60 (m, 1H), 2.28-2.05 (m, 4H), 2.01-1.89(m, 1H), 1.84-1.74 (m, 1H).

Example 122

5-{3-[(3-Chloropyridin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 3-chloro-2-fluoropyridine. MS (ESI):mass calcd. for C₁₉H₁₆ClFN₄O, 370.10; m/z found, 371.1 [M+H]⁺. ¹H NMR(600 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.00 (d, J=1.5, 1H), 7.82 (d, J=5.8,1H), 7.63 (m, 1H), 7.22 (d, J=8.3, 1H), 7.04 (s, 2H), 6.65 (s, 2H), 6.17(d, J=5.8, 1H), 2.14-2.01 (m, 4H), 1.94-1.84 (m, 1H), 1.76-1.69 (m, 1H).

Example 123

5-{3-[2-Chloro-4-(methylsulfonyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 2 hours and using2-chloro-1-fluoro-4-methylsulfonylbenzene. MS (ESI): mass calcd. forC₂₁H₁₉ClFN₃O₃S, 447.08; m/z found, 448.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.30-8.26 (m, 1H), 8.13 (d, J=2.3, 1H), 8.01 (d, J=1.5, 1H),7.85-7.74 (m, 2H), 7.38 (d, J=8.3, 1H), 6.87 (dd, J=8.7, 1.1, 1H), 6.72(s, 2H), 3.24 (s, 3H), 2.17-2.07 (m, 4H), 1.96-1.84 (m, 1H), 1.81-1.69(m, 1H).

Example 124

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using 4-chloro-2-(trifluoromethyl)pyrimidine.MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J=5.7, 1H), 8.46-8.42 (m, 1H), 8.09(d, J=1.4, 1H), 7.84 (m, 1H), 7.24 (d, J=8.3, 1H), 7.12 (d, J=5.7, 1H),4.74 (s, 2H), 3.64-3.52 (m, 1H), 2.24-2.08 (m, 4H), 2.05-1.90 (m, 1H),1.87-1.77 (m, 1H).

Example 125

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using 4-chloro-6-trifluoromethylpyrimidine.MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.48-8.42 (m, 1H), 8.09 (d,J=1.5, 1H), 7.91-7.82 (m, 1H), 7.38 (d, J=1.0, 1H), 7.28-7.22 (m, 1H),4.73 (s, 2H), 3.58 (p, J=8.8, 1H), 2.27-2.09 (m, 4H), 2.05-1.91 (m, 1H),1.88-1.76 (m, 1H).

Example 126

5-{4-Cyclobutyl-2-fluoro-3-[3-methyl-4-(methylsulfonyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 2 hours and using4-fluoro-2-methyl-1-(methylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₂H₂₂FN₃O₃S, 427.14; m/z found, 428.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.46-8.43 (m, 1H), 8.10 (d, J=1.5, 1H), 7.95 (d, J=8.8, 1H), 7.85-7.78(m, 1H), 7.27 (d, J=9.3, 1H), 6.84 (d, J=2.5, 1H), 6.78 (dd, J=8.8, 2.6,1H), 4.85 (s, 2H), 3.58 (p, J=8.9, 1H), 3.07 (s, 3H), 2.26-2.07 (m, 4H),2.00-1.90 (m, 1H), 1.87-1.75 (m, 1H).

Example 127

5-(4-Cyclobutyl-2-fluoro-3-(4-(methylsulfonyl)-2-(trifluoromethyl)phenoxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using2-chloro-5-methansulfonylbenzotrifluoride. MS (ESI): mass calcd. forC₂₂H₁₉F₄N₃O₃S, 481.11; m/z found, 482.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.46-8.41 (m, 1H), 8.28 (d, J=2.2, 1H), 8.09 (d, J=1.5, 1H), 7.96 (dd,J=8.8, 2.3, 1H), 7.89-7.83 (m, 1H), 7.30 (d, J=8.3, 1H), 6.82 (d, J=8.8,1H), 4.79 (s, 2H), 3.62 (p, J=8.8, 1H), 3.09 (s, 3H), 2.43-1.91 (m, 4H),1.88-1.69 (m, 2H).

Example 128

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 2 hours and using 5-fluoro-2-(trifluoromethyl)pyridine.MS (ESI): mass calcd. for C₂₀H₁₆F₄N₄O, 404.13; m/z found, 405.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=2.8, 1H), 8.44 (dd, J=2.2, 1.7,1H), 8.09 (d, J=1.5, 1H), 7.86-7.80 (m, 1H), 7.60 (d, J=8.7, 1H), 7.28(d, J=7.8, 1H), 7.19 (dd, J=8.7, 2.8, 1H), 4.78 (s, 2H), 3.61 (p, J=8.8,1H), 2.28-2.08 (m, 4H), 2.04-1.91 (m, 1H), 1.88-1.78 (m, 1H).

Example 129

5-{4-Cyclobutyl-2-fluoro-3-[(3-methoxypyridin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-fluoro-3-methoxypyridine. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₂, 366.15; m/z found, 367.1 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.27 (s, 1H), 8.20 (s, 1H), 7.84-7.77 (m, 1H), 7.63(dd, J=5.0, 1.4, 1H), 7.27-7.21 (m, 2H), 6.99 (dd, J=7.9, 4.9, 1H), 4.01(s, 3H), 3.74-3.61 (m, 1H), 2.25-2.11 (m, 4H), 2.01-1.88 (m, 1H),1.87-1.74 (m, 1H).

Example 130

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-amino-4-chloropyrimidine. MS (ESI):mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.48-8.45 (m, 1H), 8.15 (d, J=5.7, 1H), 8.06 (d, J=1.5,1H), 7.81-7.75 (m, 1H), 7.20 (d, J=8.3, 1H), 6.25 (d, J=5.7, 1H), 5.01(s, 2H), 4.70 (s, 2H), 3.59 (p, J=8.9, 1H), 2.30-2.07 (m, 4H), 2.04-1.90(m, 1H), 1.87-1.75 (m, 1H).

Example 131

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using 2-chloro-4-(trifluoromethyl)pyrimidine.MS (ESI): mass calcd. for C₁₉H₁₅F₄N₅O, 405.12; m/z found, 406.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=4.8, 1H), 8.45 (dd, J=2.1, 1.7,1H), 8.09 (d, J=1.5, 1H), 7.87-7.78 (m, 1H), 7.39 (d, J=4.9, 1H), 7.24(d, J=8.3, 1H), 4.68 (s, 2H), 3.70 (p, J=8.9, 1H), 2.26-2.08 (m, 4H),2.03-1.90 (m, 1H), 1.86-1.76 (m, 1H).

Example 132

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5-(methylsulfonyl)benzonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using2-fluoro-5-(methylsulfony)lbenzonitrile. MS (ESI): mass calcd. forC₂₂H₁₉FN₄O₃S, 438.12; m/z found, 439.1 [M+H]⁺. ¹H NMR (400 MHz, THF-d₈)δ 8.44 (d, J=2.3, 1H), 8.39 (dd, J=2.6, 1.5, 1H), 8.08-7.96 (m, 3H),7.37 (d, J=8.3, 1H), 6.98 (dd, J=8.9, 1.5, 1H), 6.08 (s, 2H), 3.76-3.65(m, 1H), 3.12 (s, 3H), 2.35-2.18 (m, 4H), 2.12-1.99 (m, 1H), 1.94-1.82(m, 1H).

Example 133

5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfonyl)-3-(trifluoromethyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using5-bromo-2-(methylsulfonyl)benzotrifluoride. MS (ESI): mass calcd. forC₂₂H₁₉F₄N₃O₃S, 481.11; m/z found, 482.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃)δ 8.47-8.42 (m, 1H), 8.21 (d, J=8.9, 1H), 8.10 (d, J=1.5, 1H), 7.90-7.82(m, 1H), 7.49 (d, J=2.6, 1H), 7.29 (d, J=8.3, 1H), 7.04 (dd, J=8.9, 2.5,1H), 4.75 (s, 2H), 3.57 (p, J=8.8, 1H), 3.18 (s, 3H), 2.27-2.09 (m, 4H),2.05-1.92 (m, 1H), 1.89-1.78 (m, 1H).

Example 134

5-{4-Cyclobutyl-2-fluoro-3-[(2-methylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using 4-chloro-2-methylpyrimidine. MS (ESI):mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.51-8.43 (m, 2H), 8.09 (d, J=1.3, 1H), 7.80 (m, 1H), 7.23(d, J=8.3, 1H), 6.70 (d, J=5.8, 1H), 4.71 (s, 2H), 3.59 (p, J=8.9, 1H),2.55 (s, 3H), 2.25-2.07 (m, 4H), 2.03-1.89 (m, 1H), 1.87-1.72 (m, 1H).

Example 135

5-(4-Cyclobutyl-2-fluoro-3-{[2-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 2 hours and using 4-chloro-2-isopropyl-pyrimidine. MS(ESI): mass calcd. for C₂₁H₂₃FN₆O, 394.2; m/z found, 395.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.52 (d, J=5.7, 1H), 8.47-8.44 (m, 1H), 8.10 (d,J=1.4, 1H), 7.80 (m, 1H), 7.22 (d, J=8.3, 1H), 6.73 (d, J=5.7, 1H), 4.69(s, 2H), 3.61 (p, J=8.8, 1H), 3.02 (hept, J=6.9, 1H), 2.24-2.06 (m, 4H),2.03-1.88 (m, 1H), 1.86-1.75 (m, 1H), 1.19 (d, J=6.9, 6H).

Example 136

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 3 hours and using 4-amino-6-chloropyrimidine. MS (ESI):mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.49-8.44 (m, 1H), 8.25 (d, J=0.6, 1H), 8.08 (d, J=1.5,1H), 7.81-7.74 (m, 1H), 7.21 (d, J=8.2, 1H), 5.94 (d, J=0.9, 1H), 4.97(s, 2H), 4.73 (s, 2H), 3.61 (p, J=8.8, 1H), 2.29-2.09 (m, 4H), 2.04-1.90(m, 1H), 1.87-1.77 (m, 1H).

Example 137

5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 2 hours and using 2,4-dichloropyrimidine. MS (ESI): masscalcd. for C₁₈H₁₅ClFN₅O, 371.09; m/z found, 372.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.67 (d, J=5.7, 1H), 8.25 (s, 1H), 8.02 (d, J=1.4, 1H),7.77 (m, 1H), 7.37-7.29 (m, 2H), 6.70 (s, 2H), 3.55-3.43 (m, 1H),2.17-2.00 (m, 4H), 1.98-1.83 (m, 1H), 1.81-1.68 (m, 1H).

Example 138

5-{3-[(6-Azetidin-1-ylpyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amineTrifluoroacetate Salt

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 4-azetidin-1-yl-6-chloro-pyrimidine. MS(ESI): mass calcd. for C₂₁H₂₁FN₆O, 392.18; m/z found, 393.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.46 (d, J=1.1, 1H), 8.35 (s, 1H), 8.06 (d,J=0.9, 1H), 7.87 (m, 1H), 7.24 (d, J=8.4, 1H), 5.77 (s, 1H), 4.33 (t,J=7.1, 4H), 3.57 (p, J=8.8, 1H), 2.63-2.52 (m, 2H), 2.29-2.07 (m, 4H),2.08-1.93 (m, 1H), 1.90-1.77 (m, 1H).

Example 139

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using(6-chloro-2-trifluoromethylpyrimidin-4-yl)dimethyl-amine. MS (ESI): masscalcd. for C₂₁H₂₀F₄N₆O, 448.16; m/z found, 449.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.45 (s, 1H), 8.07 (d, J=1.4, 1H), 7.82-7.74 (m, 1H), 7.22(d, J=8.3, 1H), 5.84 (s, 1H), 4.79 (s, 2H), 3.62 (p, J=8.9, 1H), 3.11(s, 6H), 2.27-2.07 (m, 4H), 2.03-1.75 (m, 2H).

Example 140

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methylpyrimidin-4-amineTrifluoroacetate Salt

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 4-amino-6-chloro-2-methylpyrimidine. MS(ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found, 367.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.25 (d, J=1.7, 1H), 8.11 (d, J=1.5, 1H), 7.82(m, 1H), 7.34 (d, J=8.2, 1H), 6.03 (s, 1H), 3.69-3.57 (m, 1H), 2.48 (s,3H), 2.33-2.13 (m, 4H), 2.12-1.97 (m, 1H), 1.92-1.81 (m, 1H).

Example 141

5-{4-Cyclobutyl-3-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using 4-chloro-6-cyclopropyl-pyrimidine. MS(ESI): mass calcd. for C₂₁H₂₀FN₅O, 377.16; m/z found, 378.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.56 (d, J=0.7, 1H), 8.47 (d, J=1.8, 1H), 8.08(d, J=1.5, 1H), 7.84-7.77 (m, 1H), 7.22 (d, J=8.3, 1H), 6.83 (d, J=1.0,1H), 4.65 (s, 2H), 3.59 (p, J=9.0, 1H), 2.28-2.09 (m, 4H), 2.04-1.89 (m,2H), 1.87-1.75 (m, 1H), 1.21-1.15 (m, 2H), 1.13-1.05 (m, 2H).

Example 142

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using4-chloro-6-(methoxymethyl)pyrimidin-2-amine. MS (ESI): mass calcd. forC₂₀H₂₁FN₆O₂, 396.17; m/z found, 397.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.51-8.45 (m, 1H), 8.06 (d, J=1.5, 1H), 7.81-7.74 (m, 1H), 7.20 (d,J=8.3, 1H), 6.37 (s, 1H), 5.00 (s, 2H), 4.70 (s, 2H), 4.34 (s, 2H),3.66-3.53 (m, 1H), 3.47 (s, 3H), 2.30-2.07 (m, 4H), 2.04-1.90 (m, 1H),1.87-1.74 (m, 1H).

Example 143

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-chloropyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-amino-4,6-dichloropyrimidine. MS(ESI): mass calcd. for C₁₈H₁₆ClFN₆O, 386.10; m/z found, 387.0 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.30-8.23 (m, 2H), 7.77 (m, 1H), 7.23 (d, J=8.2,1H), 6.29 (d, J=2.6, 1H), 3.64-3.52 (m, 1H), 2.31-2.21 (m, 2H),2.21-2.09 (m, 2H), 2.08-1.95 (m, 1H), 1.90-1.78 (m, 1H).

Example 144

5-{4-Cyclobutyl-2-fluoro-3-[(2-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° C. via microwave irradiation forone hour and using 4-chloro-2-phenylpyrimidine. MS (ESI): mass calcd.for C₂₄H₂₀FN₅O, 413.16; m/z found, 414.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃)δ 8.68 (d, J=5.7, 1H), 8.50-8.46 (m, 1H), 8.24-8.18 (m, 2H), 8.09 (d,J=1.5, 1H), 7.88-7.81 (m, 1H), 7.44-7.33 (m, 3H), 7.26 (m, 1H), 6.86 (d,J=5.6, 1H), 4.71 (s, 2H), 3.63 (p, J=8.9, 1H), 2.25-2.10 (m, 4H),1.99-1.88 (m, 1H), 1.83-1.75 (m, 1H).

Example 145

5-{4-Cyclobutyl-2-fluoro-3-[(6-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using 4-chloro-6-phenylpyrimidine. MS (ESI):mass calcd. for C₂₄H₂₀FN₅O, 413.16; m/z found, 414.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.82 (d, J=1.0, 1H), 8.52-8.46 (m, 1H), 8.14-8.06 (m, 3H),7.88-7.80 (m, 1H), 7.58-7.48 (m, 3H), 7.39 (d, J=1.0, 1H), 7.25 (d,J=8.8, 1H), 4.69 (s, 2H), 3.63 (p, J=8.9, 1H), 2.29-2.10 (m, 4H),2.05-1.89 (m, 1H), 1.87-1.75 (m, 1H).

Example 146

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-benzylpyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 6-amino-2-benzyl-4-chloropyrimidine. MS(ESI): mass calcd. for C₂₅H₂₃FN₆O, 442.19; m/z found, 443.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.32 (m, 1H), 8.08 (m, 1H), 7.69 (t, J=7.8, 1H),7.37 (s, 1H), 7.30-7.13 (m, 5H), 5.62 (s, 1H), 3.90 (s, 2H), 3.63-3.52(m, 1H), 2.26-2.04 (m, 4H), 2.02-1.88 (m, 1H), 1.85-1.74 (m, 1H).

Example 147

5-(4-Cyclobutyl-2-fluoro-3-{[6-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 4-chloro-6-isopropyl-pyrimidine. MS(ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.18; m/z found, 380.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.68 (d, J=0.9, 1H), 8.49-8.43 (m, 1H), 8.08 (d,J=1.5, 1H), 7.84-7.78 (m, 1H), 7.23 (d, J=8.3, 1H), 6.86 (d, J=0.5, 1H), 4.70 (s, 2H), 3.60 (p, J=8.9, 1H), 3.02 (hept, J=6.9, 1H), 2.26-2.08(m, 4H), 2.04-1.89 (m, 1H), 1.87-1.77 (m, 1H), 1.34 (d, J=6.9, 6H).

Example 148

3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonitrile

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and using5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonitrile. MS(ESI): mass calcd. for C₂₀H₁₆F₄N₆O, 432.13; m/z found, 433.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.46 (dd, J=2.2, 1.6, 1H), 8.06 (d, J=1.5, 1H),7.91 (m, 1H), 7.30-7.20 (m, 1H), 4.76 (s, 2H), 3.95 (s, 3H), 3.74 (p,J=8.8, 1H), 2.38-2.19 (m, 4H), 2.14-1.99 (m, 1H), 1.98-1.85 (m, 1H).

Intermediate C

tert-Butyl-(2-((2-chloropyrimidin-4-yl)amino)ethyl)carbamateIntermediate D

tert-Butyl-(2-((4-chloropyrimidin-2-yl)amino)ethyl)carbamate

2,4-Dichloropyrimidine (1.0 g, 6.7 mmol), tert-butylN-(2-aminoethyl)carbamate (1.06 mL, 6.71 mmol) and triethylamine (1.12mL, 8.05 mmol) were partially dissolved in acetonitrile (22.5 mL). Themixture was stirred at room temperature for 14 hours before dilutingwith water and extracting with DCM. The DCM extract was dried overNa₂SO₄, filtered and concentrated to dryness. The crude mixture waspurified by FCC to givetert-butyl-(2-((2-chloropyrimidin-4-yl)amino)ethyl)carbamate (1.07 g,58%) and tert-butyl-(2-((4-chloropyrimidin-2-yl)amino)ethyl)carbamate(280 mg, 15%).

Example 149

tert-Butyl[2-({2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-yl}amino)ethyl]carbamate

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and Intermediate C. MS (ESI): mass calcd. forC₂₅H₃₀FN₇O₃, 495.24; m/z found, 496.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.43 (s, 1H), 8.14 (d, J=5.6, 1H), 8.07 (s, 1H), 7.73 (m, 1H), 7.19 (d,J=8.3, 1H), 6.20 (d, J=5.6, 1H), 5.51 (s, 1H), 5.03 (s, 1H), 4.81 (s,2H), 3.66-3.53 (m, 1H), 3.25 (d, J=52.0, 4H), 2.31-2.05 (m, 4H),2.05-1.89 (m, 1H), 1.87-1.72 (m, 1H), 1.39 (s, 9H).

Example 150

N-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}ethane-1,2-diamine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 1 hour and Intermediate D. MS (ESI): mass calcd. forC₂₀H₂₂FN₇O, 395.19; m/z found, 396.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.30-8.25 (m, 1H), 8.05 (d, J=1.5, 1H), 7.84 (s, 1H), 7.67 (m, 1H), 7.25(d, J=8.2, 1H), 6.25 (d, J=5.8, 1H), 3.66 (p, J=8.9, 1H), 3.26 (t,J=6.2, 2H), 2.70 (s, 2H), 2.29-2.09 (m, 4H), 2.06-1.93 (m, 1H),1.88-1.77 (m, 1H).

Example 151

Methyl2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylateTrifluoroacetate Salt

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 80° Celsius via microwaveirradiation for 2 hours and methyl 2-chloropyrimidine-4-carboxylate (280mg, 15%). MS (ESI): mass calcd. for C₂₀H₁₈FN₅O₃, 395.14; m/z found,396.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=4.9, 1H), 8.37 (d,J=1.3, 1H), 8.11 (d, J=1.2, 1H), 7.86 (m, 1H), 7.80 (d, J=4.9, 1H),7.30-7.24 (m, 1H), 4.67 (s, 2H), 4.04 (s, 3H), 3.76-3.63 (m, 1H),2.27-2.07 (m, 4H), 2.04-1.88 (m, 1H), 1.87-1.74 (m, 1H).

Example 152

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylicAcid

Title compound was found as an additional product in the formation ofmethyl2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylate,Example 151. MS (ESI): mass calcd. for C₁₉H₁₆FN₅O₃, 381.12; m/z found,382.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.78 (d, J=4.9, 1H), 8.25 (d,J=1.5, 1H), 8.21 (m, 1H), 7.85-7.79 (m, 2H), 7.30 (d, J=8.3, 1H),3.73-3.61 (m, 1H), 2.24-2.08 (m, 4H), 2.06-1.91 (m, 1H), 1.86-1.75 (m,1H).

Example 153

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoic acid

The title compound was prepared using analogous conditions described inExample 85 using Example 103 as a starting material. MS (ESI): masscalcd. for C₂₁H₁₈FN₃O₃, 379.13; m/z found, 380.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.24 (s, 1H), 8.16 (s, 1H), 8.03-7.97 (m, 2H), 7.78 (m,1H), 7.35 (d, J=8.3, 1H), 6.92 (d, J=8.8, 2H), 3.69-3.57 (m, 1H),2.24-2.11 (m, 4H), 2.04-1.90 (m, 1H), 1.88-1.76 (m, 1H).

Example 154

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylicAcid

The title compound was prepared using analogous conditions described inExample 85 using Example 107 as a starting material. MS (ESI): masscalcd. for C₂₀H₁₇FN₄O₃, 380.13; m/z found, 381.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.59-8.53 (m, 1H), 8.27 (dd, J=8.6, 2.4, 1H), 8.21-8.16(m, 1H), 7.98 (d, J=1.5, 1H), 7.67 (m, 1H), 7.26-7.17 (m, 2H), 2.08-1.95(m, 4H), 1.90-1.76 (m, 1H), 1.73-1.61 (m, 1H).

Example 155

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzamide

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile (30mg, 0.083 mmol) was dissolved in TFA (0.75 mL) and treated with conc.H₂SO₄ (0.25 mL). The mixture was stirred at room temperature for 20hours. The mixture was then poured over ice water (100 mL) and theaqueous layer extracted with 10% MeOH/DCM. The water layer was adjustedto pH 7 with aqueous NaOH and extracted again 10% MeOH/DCM. The combinedorganic extracts were dried and concentrated to dryness. The crudeproduct was purified by FCC to afford the title compound (28 mg, 89%).MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂, 378.15; m/z found, 379.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.26 (s, 1H), 8.05 (s, 1H), 7.89-7.83 (m, 2H),7.77-7.70 (m, 1H), 7.33 (d, J=8.3, 1H), 6.94-6.87 (m, 2H), 3.69-3.57 (m,1H), 2.24-2.10 (m, 4H), 2.04-1.89 (m, 1H), 1.87-1.76 (m, 1H).

Example 156

N′-{4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}-N,N-dimethylethane-1,2-diamineHydrochloride

5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine(77 mg, 0.21 mmol) was partially dissolved inN,N-dimethylethylenediamine (0.23 mL) and heated via microwaveirradiation at 120° Celsius for 2 hours. The reaction mixture wassubjected to direct HPLC purification. The post-HPLC material was thensubjected to FCC to afford the title compound. The final product wasconverted to the HCl salt by dissolving it in MeOH and treating thesolution with HCl (1.0 M, 0.42 mL) in water. The reaction mixture wasthen concentrated to dryness to give the title compound (13 mg, 13%). MS(ESI): mass calcd. for C₂₂H₂₆FN₇O, 423.22; m/z found, 424.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.50-8.45 (m, 1H), 8.06 (d, J=1.5, 1H), 7.93 (s,1H), 7.79-7.71 (m, 1H), 7.20 (d, J=8.3, 1H), 6.08 (d, J=5.9, 1H), 5.74(s, 1H), 4.69 (s, 2H), 3.78-3.65 (m, 1H), 3.37 (s, 2H), 2.51 (t, J=5.9,2H), 2.30-2.07 (m, 11H), 2.04-1.88 (m, 1H), 1.86-1.73 (m, 1H).

Example 157

2-[3-(5-Aminopyrazin-1-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating for 2 hours at 80° Celsius and usingIntermediate B and 2-chloropyrimidine-4-carboxamide. MS (ESI): masscalcd. for C₁₉H₁₇FN₆O₂, 380.14; m/z found, 381.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.84-8.78 (d, J=4.9, 1H), 8.30-8.21 (m, 2H), 8.06-7.97(d, J=1.5, 2H), 7.80-7.71 (m, 2H), 7.35-7.28 (d, J=8.3, 1H), 6.78-6.66(s, 2H), 3.64-3.51 (m, 1H), 2.16-2.01 (m, 4H), 1.98-1.84 (m, 1H),1.81-1.66 (m, 1H).

Example 158

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-5-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating for 18 hours at 140° Celsius usingIntermediate B and 5-amino-2-chloropyrimidine. MS (ESI): mass calcd. forC₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.17-8.13 (m, 1H), 7.95 (d, J=1.5, 1H), 7.92 (s, 2H), 7.62-7.54 (m, 1H),7.15 (d, J=8.3, 1H), 3.61-3.49 (m, 1H), 2.16-1.98 (m, 4H), 1.96-1.80 (m,1H), 1.77-1.63 (m, 1H).

Example 159

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine

The title compound was prepared using analogous conditions described inStep D of Intermediate A using(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and2-amino-5-bromopyrimidine. MS (ESI): mass calcd. for C₁₅H₁₆FN₃O, 273.13;m/z found, 274.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=1.4, 2H),7.10 (d, J=8.2, 1H), 7.08-6.99 (m, 1H), 5.24 (s, 2H), 3.90 (d, J=1.4,3H), 3.88-3.74 (m, 1H), 2.41-2.31 (m, 2H), 2.22-1.99 (m, 3H), 1.93-1.82(m, 1H).

Intermediate E

3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol

To a 200 mL flask were added a stir bar,5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine (729 mg, 2.7mmol) and dry DCM (27 mL). The flask was purged with nitrogen, stirreduntil homogeneous and cooled to −78° Celsius. The resulting solution wascharged with boron tribromide (1.0 M in DCM, 8.09 mL). The mixture waskept at −78° Celsius for 30 min before warming to room temperature.After 5 hours, the reaction mixture was poured into a 500 mL mixture ofice and saturated NaHCO₃. This mixture was partitioned between EtOAc andthe aqueous layer. The EtOAc layer was isolated, dried and concentratedto dryness. The resulting solid was purified by FCC to yield the titlecompound (602 mg, 87%). MS (ESI): mass calcd. for C₁₄H₁₄FN₃O, 259.11;m/z found, 260.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (d, J=2.0,1H), 8.39 (d, J=1.4, 2H), 7.04 (d, J=8.0, 1H), 6.89 (m, 1H), 6.83 (s,2H), 3.80-3.65 (m, 1H), 2.34-2.20 (m, 2H), 2.15-1.89 (m, 3H), 1.89-1.74(m, 1H).

Example 160

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

To a 5 mL vial containing a stir bar,3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol (80 mg, 0.31 mmol)and 2-chloropyrimidine (41 mg, 0.34 mmol) were added Cs₂CO₃ (203 mg,0.62 mmol) and DMSO (0.8 mL). The resultant mixture was stirred at 120°Celsius for approximately 1 hour via microwave irradiation. The reactionmixture was cooled to room temperature before passing the mixturethrough a syringe filter and subjecting the filtrate to FCC to affordthe title compound (81 mg, 78%). MS (ESI): mass calcd. for C₁₈H₁₆FN₅O,337.13; m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d,J=4.8, 2H), 8.50 (d, J=1.0, 2H), 7.31-7.19 (m, 2H), 7.09-7.05 (m, 1H),5.40 (s, 2H), 3.71 (p, J=8.9, 1H), 2.28-2.07 (m, 4H), 2.03-1.89 (m, 1H),1.86-1.74 (m, 1H).

Example 161

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 with DMF as the solvent heating via microwaveirradiation for 2 hours and using 4-amino-2-chloropyrimidine. MS (ESI):mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.50 (d, J=1.3, 2H), 8.01 (d, J=5.7, 1H), 7.25-7.16 (m,2H), 6.17 (d, J=5.7, 1H), 5.17 (s, 2H), 5.05 (s, 2H), 3.77-3.64 (m, 1H),2.33-2.07 (m, 4H), 2.04-1.90 (m, 1H), 1.87-1.74 (m, 1H).

Example 162

4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating via microwave irradiation for 2 hoursand using 4-chloro-6-(methoxymethyl)pyrimidin-2-amine. MS (ESI): masscalcd. for C₂₀H₂₁FN₆O₂, 396.17; m/z found, 397.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.48 (d, J=1.0, 2H), 7.25-7.15 (m, 2H), 6.38 (s, 1H), 5.30(s, 2H), 5.08 (s, 2H), 4.35 (s, 2H), 3.66-3.53 (m, 1H), 3.48 (s, 3H),2.29-2.06 (m, 4H), 2.05-1.89 (m, 1H).

Example 163

5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating to 80° Celsius on a hotplate for 3hours and using 2-chloro-4-methylpyrimidine. MS (ESI): mass calcd. forC₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.50 (d, J=1.3, 2H), 8.33 (d, J=5.0, 1H), 7.26-7.18 (m, 2H), 6.92 (d,J=5.0, 1H), 5.29 (s, 2H), 3.71 (p, J=8.9, 1H), 2.52 (s, 3H), 2.27-2.07(m, 4H), 2.02-1.90 (m, 1H), 1.85-1.73 (m, 1H).

Example 164

5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine

To a 5 mL vial containing a stir bar,3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol (88 mg, 0.34 mmol)and 4-amino-6-chloropyrimidine (46 mg, 0.36 mmol) were added K₂CO₃ (70mg, mg, 0.51 mmol), 18-crown-6 (9 mg, 0.03 mmol) and DMA (0.68 mL). Theresultant mixture was stirred at 120° Celsius for approximately 3 hoursbefore cooling to room temperature and passing it through a syringefilter and subjecting the filtrate to FCC to afford the title compound(42 mg, 35%). MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found,353.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=1.1, 2H), 8.23 (s,1H), 7.26-7.16 (m, 2H), 5.99 (s, 1H), 5.25 (s, 2H), 5.01 (s, 2H), 3.61(p, J=8.9, 1H), 2.31-2.08 (m, 4H), 2.00-1.90 (m, 1H), 1.89-1.78 (m, 1H).

Example 165

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating to 80° Celsius for 3 hours and using2-chloro-4-isopropyl-pyrimidine. MS (ESI): mass calcd. for C₂₁H₂₂FN₅O,379.180; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d,J=1.3, 2H), 8.38 (d, J=5.1, 1H), 7.26-7.18 (m, 2H), 6.92 (d, J=5.1, 1H),5.19 (s, 2H), 3.79-3.66 (m, 1H), 3.03-2.92 (m, 1H), 2.27-2.06 (m, 4H),2.03-1.89 (m, 1H), 1.85-1.74 (m, 1H), 1.28 (d, J=6.9, 6H).

Example 166

4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating the reaction for 18 hours and using2-amino-4-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O,352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d,J=1.2, 2H), 8.16 (d, J=5.6, 1H), 7.24 (d, J=7.1, 1H), 7.19 (d, J=8.2,1H), 6.27 (d, J=5.7, 1H), 5.19 (s, 2H), 4.98 (s, 2H), 3.65-3.54 (m, 1H),2.29-2.07 (m, 4H), 2.04-1.91 (m, 1H), 1.88-1.76 (m, 1H).

Example 167

5-{4-Cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating to 80° Celsius for 3 hours and using2-chloro-4,6-dimethylpyrimidine. MS (ESI): mass calcd. for C₂₀H₂₀FN₅O,365.17; m/z found, 366.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d,J=1.1, 2H), 7.25-7.16 (m, 2H), 6.76 (s, 1H), 5.19 (s, 2H), 3.77-3.65 (m,1H), 2.39 (s, 6H), 2.27-2.06 (m, 4H), 2.01-1.88 (m, 1H), 1.85-1.75 (m,1H).

Example 168

4-(3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isopropylpyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating the reaction for 18 hours and using2-amino-4-chloro-6-isopropylpyrimidine. MS (ESI): mass calcd. forC₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.45 (s, 1H), 8.04 (s, 1H), 7.76 (m, 1H), 7.20 (d, J=8.2 Hz, 1H), 6.12(s, 1H), 5.03 (s, 2H), 4.75 (s, 2H), 3.60 (p, J=8.8, 1H), 2.85-2.71 (m,1H), 2.30-2.06 (m, 4H), 2.05-1.90 (m, 1H), 1.89-1.74 (m, 1H), 1.24 (d,J=6.9, 6H).

Example 169

2-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating at 80° Celsius via microwave radiationfor 2 hours and using 2-chloropyrimidine-4-carboxamide. MS (ESI): masscalcd. for C₁₉H₁₇FN₆O₂, 380.14; m/z found, 381.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.81 (d, J=4.9, 1H), 8.44 (s, 2H), 8.21 (s, 1H), 7.98(s, 1H), 7.77 (d, J=4.9, 1H), 7.52-7.42 (m, 1H), 7.30 (d, J=8.2, 1H),6.89 (s, 2H), 3.63-3.51 (m, 1H), 2.15-2.00 (m, 4H), 1.99-1.84 (m, 1H),1.81-1.68 (m, 1H).

Example 170

5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amineTrifluoroacetate Salt

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating the reaction at 140° Celsius for 18hours and using 6-chloro-4-pyrimidinyl methyl ether. Both,(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-aminetrifluoroacetate salt and6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-oltrifluoroacetate (Example 171), were isolated from this reaction. MS(ESI): mass calcd. for C₁₉H₁₈FN₅O₂, 367.14; m/z found, 368.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.41-8.36 (d, J=1.2, 2H), 8.33-8.26 (s, 1H),7.44-7.34 (m, 1H), 7.26-7.17 (d, J=8.1, 1H), 7.03-6.88 (s, 1H),5.73-5.67 (s, 1H), 3.54-3.39 (m, 1H), 2.18-1.96 (m, 4H), 1.95-1.82 (m,1H), 1.76-1.64 (m, 1H), 3.32-3.26 (m, 3H).

Example 171

6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-olTrifluoroacetate Salt

Formed as an additional product in the formation of5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine(Example 170). MS (ESI): mass calcd. for C₁₈H₁₆FN₅O₂, 353.13; m/z found,354.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 8.42 (d, J=1.2,2H), 8.07-8.01 (m, 1H), 7.42-7.34 (m, 1H), 7.20 (d, J=8.2, 1H),7.18-6.94 (m, 2H), 5.62 (s, 1H), 3.54-3.39 (m, 1H), 2.19-1.96 (m, 4H),1.96-1.81 (m, 1H), 1.77-1.64 (m, 1H).

Example 172

6-Amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared using analogous conditions described inIntermediate A's Step D using(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and2-amino-5-bromo-6-cyanopyrazine. MS (ESI): mass calcd. for C₁₆H₁₅FN₄O,298.12; m/z found, 299.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 8.21 (s, 1H),7.21-7.16 (m, 1H), 7.16-7.10 (m, 1H), 3.86-3.76 (m, 1H), 2.39-2.30 (m,2H), 2.21-2.09 (m, 2H), 2.09-1.98 (m, 1H), 1.91-1.81 (m, 1H).

Example 173

6-Amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared using analogous conditions described inIntermediate B utilizing6-amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₁₅H₁₃FN₄O, 284.11; m/z found, 285.1 [M+H]⁺.¹H NMR (600 MHz, CD₃OD) δ 8.17 (s, 1H), 7.13-7.07 (m, 1H), 6.95-6.90(dd, J=8.0, 6.8, 1H), 3.89-3.79 (m, 1H), 2.43-2.33 (m, 2H), 2.25-2.14(m, 2H), 2.13-2.01 (m, 1H), 1.92-1.83 (m, 1H).

Example 174

3-{[3-(5-Amino-3-cyanopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoicAcid

The title compound was prepared using analogous conditions described inExample 1 using6-amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrileand methyl 3-(bromomethyl)benzoate. MS (ESI): mass calcd. forC₂₃H₁₉FN₄O₃, 418.14; m/z found, 419.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆)δ 8.22 (s, 1H), 8.09-8.05 (m, 1H), 7.96-7.91 (m, 1H), 7.73-7.68 (m, 1H),7.57-7.52 (m, 1H), 7.36 (s, 2H), 7.33-7.26 (m, 2H), 5.09 (s, 2H),3.80-3.70 (p, J=9.0, 1H), 2.26-2.15 (m, 2H), 2.15-2.04 (m, 2H),1.99-1.88 (m, 1H), 1.84-1.73 (m, 1H).

Example 175

2-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared using analogous conditions described inIntermediate A Step D using(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and5-bromo-4,7-diazaindole. MS (ESI): mass calcd. for C₁₇H₁₆FN₃O, 297.13;m/z found, 298.1 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ 9.43-9.28 (s, 1H),8.72-8.67 (d, J=2.6, 1H), 7.67-7.58 (m, 2H), 7.19-7.13 (m, 1H),6.82-6.78 (dd, J=3.7, 1.9, 1H), 3.96-3.89 (d, J=1.3, 3H), 3.89-3.77 (m,1H), 2.42-2.32 (m, 2H), 2.21-2.11 (m, 2H), 2.10-1.99 (m, 1H), 1.92-1.83(m, 1H).

Example 176

6-Cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol

The title compound was prepared using analogous conditions described inIntermediate B starting with2-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine. MS(ESI): mass calcd. for C₁₆H₁₄FN₃O, 283.11; m/z found, 284.0 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) 9.16 (s, 1H), 8.67 (d, J=2.6, 1H), 7.69-7.61 (m,1H), 7.49-7.39 (m, 1H), 7.14 (d, J=8.1, 1H), 6.84-6.77 (m, 1H), 5.48 (s,1H), 3.89-3.76 (m, 1H), 2.48-2.34 (m, 2H), 2.30-2.15 (m, 2H), 2.16-1.99(m, 1H), 1.96-1.82 (m, 1H).

Example 177

2-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-5H-pyrrolo[2,3-b]pyrazineTrifluoroacetate Salt

To a 5 mL vial containing a stir bar,6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol (40 mg,0.14 mmol) and 4-(trifluoromethyl)benzyl bromide (41 mg, 0.17 mmol) wereadded KOH (24 mg, 0.42 mmol) and 0.78 mL of DMSO. The resultant mixturewas stirred at rt for approximately 20 hours. The mixture was passedthrough a syringe filter and the filtrate subjected to HPLC purificationaffording the title compound (12 mg, 15%). MS (ESI): mass calcd. forC₂₄H₁₉F₄N₃O, 441.15; m/z found, 442.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.95 (s, 1H), 8.64 (d, J=2.0, 1H), 7.76 (dd, J=3.5, 2.7, 1H), 7.74-7.64(m, 3H), 7.61 (d, J=8.1, 2H), 7.28-7.23 (m, 1H), 6.92 (dd, J=3.7, 1.9,1H), 5.14 (s, 2H), 3.82 (p, J=8.7, 1H), 2.37-2.26 (m, 2H), 2.25-2.11 (m,2H), 2.11-1.97 (m, 1H), 1.94-1.79 (m, 1H).

Example 178

2-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine

Step A

2-(3-(Benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b] was preparedusing procedures similar to those described in Example 216 utilizing5-bromo-4,7-diazaindole. MS (ESI): mass calcd. for C₁₉H₁₃ClFN₃O, 353.07;m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.70(d, J=2.9, 1H), 7.72-7.65 (m, 2H), 7.58-7.51 (m, 2H), 7.44-7.30 (m, 4H),6.82 (dd, J=3.7, 1.9, 1H), 5.20 (s, 2H).

Step B

The title compound was prepared using analogous conditions described inExample 83 using2-(3-(benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS(ESI): mass calcd. for C₂₃H₂₀FN₃O, 373.16; m/z found, 374.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 10.09 (s, 1H), 8.66 (s, 1H), 7.76-7.65 (m, 2H),7.51-7.46 (m, 2H), 7.45-7.33 (m, 3H), 7.24 (d, J=8.3, 1H), 6.88 (m, 1H),5.09 (s, 2H), 3.88-3.76 (m, 1H), 2.36-2.26 (m, 2H), 2.22-2.09 (m, 2H),2.09-1.95 (m, 1H), 1.91-1.81 (m, 1H).

Example 179

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine HydrochlorideSalt

Solid (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (350 mg, 1.56mmol), 2-amino-5-bromopyridine (270 mg, 1.56 mmol), andPd(dppf)Cl₂.CH₂Cl₂ (102 mg, 0.16 mmol) were placed in a round-bottomedflask under nitrogen. The flask was then charged with sparged THF (7mL), KOH (760 mg, 14 mmol), and water (2 mL). The reaction mixture wasstirred at room temperature overnight, then treated with EtOAc (20 mL).The mixture was dried, filtered, and concentrated to dryness. Theresidue was subjected to FCC to give pure title compound. The materialwas converted to a hydrochloride salt by dissolving in ether (10 mL)followed by adding a solution of 4 M HCl in 1,4-dioxane (0.3 mL). Theprecipitate was collected by filtration, washed with ether, and dried toyield the title compound (330 mg, 78%). MS (CI): mass calcd. forC₁₆H₁₇FN₂O, 272.13; m/z found, 273.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ14.12 (s, 1H), 8.31-8.05 (m, J=22.9, 5.6, 4H), 7.28-7.19 (m, 2H), 7.08(d, J=9.3, 1H), 3.83 (d, J=0.8, 3H), 3.80-3.71 (m, 1H), 2.35-2.25 (m,2H), 2.16-1.96 (m, 3H), 1.87-1.77 (m, J=18.5, 8.7, 1H).

Intermediate F

5-(4-Cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine

A solution consisting of5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine (333 mg, 1.08mmol) and DCM (10 mL) was cooled to −78° Celsius, and then treated with1 M BBr₃ in DCM (3.3 mL, 3.3 mmol) dropwise. The solution was maintainedat −78° Celsius for 30 min, then warmed to room temperature and stirredovernight. The reaction mixture was poured into a beaker containing iceand saturated NaHCO₃, then extracted with EtOAc. The organic phase wasisolated, dried and concentrated to dryness to afford the titlecompound. MS (CI): mass calcd. for C₁₅H₁₅FN₂O, 258.12; m/z found, 259.2[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 9.29 (d, J=2.0, 1H), 8.05 (s, 1H),7.59-7.46 (m, 1H), 7.01 (d, J=8.0, 1H), 6.82 (m, 1H), 6.52 (dd, J=8.6,0.6, 1H), 6.10 (s, 2H), 3.77-3.66 (m, J=8.6, 1H), 2.32-2.21 (m, 2H),2.14-2.02 (m, 2H), 2.02-1.90 (m, 1H), 1.85-1.72 (m, 1H).

Example 180

5-Methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoate

A mixture of 5-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine(50 mg, 0.19 mmol), Cs₂CO₃ (190 mg, 0.58 mmol), methyl4-(bromomethyl)benzoate (56 mg, 0.25 mmol), and DMF (1 mL) was stirredat room temperature for 16 hours. The mixture was poured into water andextracted with EtOAc. The organic phase was isolated, dried,concentrated to dryness and the residue subjected to FCC to give thetitle compound (74 mg, 94%). MS (CI): mass calcd. for C₂₄H₂₃FN₂O₃,406.17; m/z found, 407.3 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ 8.09 (s,1H), 8.05-7.97 (m, 2H), 7.62 (d, J=8.4, 2H), 7.57 (d, J=8.6, 1H),7.23-7.12 (m, 2H), 6.52 (dd, J=8.6, 0.6, 1H), 6.15 (s, 2H), 5.10 (s,2H), 3.87 (s, 3H), 3.79-3.67 (m, J=8.8, 1H), 2.25-2.15 (m, 2H),2.14-2.02 (m, 2H), 2.00-1.89 (m, 1H), 1.83-1.72 (m, J=8.9, 8.4, 1H).

Example 181

4-((3-(6-Aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoicacid

A mixture of5-methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)-benzoate(54 mg, 0.13 mmol), KOH (2 M, 0.3 mL), THF (2 mL), and MeOH (1 mL) wasstirred 16 hours at room temperature. The mixture was concentrated todryness, treated with water (2 mL) and HCl (1M, 0.75 mL). The resultingprecipitate was collected, washed with water, and dried to yield thetitle compound (0.48 mg, 92%). MS (CI): mass calcd. for C₂₃H₂₁FN₂O₃,392.15; m/z found, 393.3 [M+H]⁺.

Intermediate F′

5-Bromo-1H-imidazo-[4,5-b]pyrazine

To a 50 mL round bottom flask fitted with a reflux condenser, undernitrogen were added 5-bromopyrazine-2,3-diamine (400 mg, 2.1 mmol) andtriethyl orthoformate (3.1 g, 21.2 mmol). The mixture was heated toreflux and stirred for 24 h. The reaction was cooled to rt, concentratedto dryness and the residue purified by HPLC to give 320 mg (76% yield)of the title compound. MS (ESI): mass calcd. for C₅H₃BrN₄, 197.95; m/zfound, 199.1 [M+H]⁺.

Example 182

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyrazine

To a mixture of 5-bromo-1H-imidazo-[4,5-b]pyrazine (50 mg, 0.25 mmol),(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (67 mg, 0.30 mmol)and [1,1′bis(diphenylphosphino)-ferrocene]dichloropalladium(II).CH₂Cl₂(10 mg, 0.01 mmol) in a microwave vial were added acetonitrile (2.0 mL)and sodium bicarbonate solution (saturated 2.0 mL). The reaction wasde-gassed with nitrogen, vial capped and irradiated via microwaveradiation for 90 min at 110° Celsius before cooling to rt. The reactionmixture was diluted with ethyl acetate (50 mL) and washed with water (25mL) and brine (25 mL). dried (Na₂SO₄) and concentrated to dryness. Thecrude residue was purified by HPLC yielding the title compound (30 mg,40%). MS (ESI): mass calcd. for C₁₆H₁₅FN₄O, 298.12; m/z found, 299.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) Complex due to the presence of multipleconformations on the NMR time-scale, peaks listed for identificationpurposes only: δ 11.38 (s), 10.85 (s), 9.02 (d, J=2.03), 8.91 (d,J=2.10), 8.53 (s), 7.87-7.77 (m), 7.58-7.49 (m), 7.26-7.17 (m), 3.96(s), 3.94 (s), 3.92-3.80 (m), 2.51-2.32 (m), 2.30-1.98 (m), 1.97-1.78(m).

Example 183

6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine

The title compound was prepared using methods analogous to thosedescribed in Example 182 using(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and6-bromo-3H-imidazo[4,5-b]pyridine. MS (ESI): mass calcd. for C₁₇H₁₆FN₃O,297.13; m/z found, 298.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 11.41 (s,1H), 8.62 (s, 1H), 8.30 (s, 2H), 7.22-7.12 (m, 2H), 3.94 (s, 3H),3.92-3.78 (m, 1H), 2.48-2.33 (m, 2H), 2.29-2.00 (m, 3H), 1.97-1.79 (m,1H).

Example 184

7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described inExample 1 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. MS (ESI): mass calcd.for C₁₈H₁₉FN₂O₂, 314.14; m/z found, 315.2 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.86 (s, 1H), 7.19 (s, 1H), 7.09-7.02 (m, 2H), 5.44 (s, 1H),4.28-4.19 (m, 2H), 3.89 (s, 3H), 3.84-3.75 (m, 1H), 3.59 (s, 2H),2.39-2.31 (m, 2H), 2.20-2.10 (m, 2H), 2.09-2.00 (m, 1H), 1.90-1.82 (m,1H).

Example 185

6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol

A solution of7-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(0.103 g, 0.328 mmol) in CH₂Cl₂ (10 mL) was cooled to −78° Celsius andtreated drop wise with BBr₃ (1 M in CH₂Cl₂, 1.6 mL). The reactionmixture was stirred for 16 hours with gradual warming to roomtemperature. The mixture was concentrated to dryness, and the residuepurified by HPLC to give title compound (81 mg, 82%). MS (ESI): masscalcd. for C₁₇H₁₇FN₂O₂, 300.13; m/z found, 301.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 7.84 (m, 1H), 7.20 (m, 1H), 7.02 (d, J=8.1, 1H), 6.83 (m,1H), 4.27-4.23 (m, 2H), 3.88-3.74 (m, 1H), 3.63-3.52 (m, 2H), 2.42-2.32(m, 2H), 2.23-2.10 (m, 2H), 2.08-2.00 (m, 1H), 1.92-1.80 (m, 1H).

Example 186

7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland (bromomethyl)benzene. MS (ESI): mass calcd. for C₂₄H₂₃FN₂O₂, 390.17;m/z found, 391.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.72 (s, 1H),7.64-7.61 (m, 1H), 7.47-7.42 (m, 2H), 7.41-7.31 (m, 3H), 7.23-7.16 (m,2H), 5.05 (s, 2H), 4.36 (t, J=4.6, 2H), 3.81-3.73 (m, 1H), 3.73-3.65 (m,2H), 2.31-2.20 (m, 2H), 2.17-1.95 (m, 3H), 1.87-1.79 (m, 1H).

Example 187

3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 3-(bromomethyl)benzonitrile. MS (ESI): mass calcd. for C₂₅H₂₂FN₃O₂,415.17; m/z found, 416.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.82 (s, 1H),7.78 (d, J=7.8, 1H), 7.74-7.70 (m, 2H), 7.68-7.64 (m, 1H), 7.59 (m, 1H),7.27-7.20 (m, 2H), 5.12 (s, 2H), 4.40-4.33 (m, 2H), 3.84-3.68 (m, 3H),2.34-2.24 (m, 2H), 2.20-1.97 (m, 3H), 1.90-1.81 (m, 1H).

Example 188

7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 1-(bromomethyl)-3-(methylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₅H₂₅FN₂O₄S, 468.15; m/z found, 469.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.06 (s, 1H), 7.94 (d, J=7.9, 1H), 7.81 (d, J=7.7, 1H), 7.72 (s, 1H),7.70-7.61 (m, 2H), 7.25-7.19 (m, 2H), 5.18 (s, 2H), 4.38-4.33 (m, 2H),3.84-3.73 (m, 1H), 3.72-3.67 (m, 2H), 3.12 (s, 3H), 2.34-2.23 (m, 2H),2.18-1.98 (m, 3H), 1.89-1.79 (m, 1H).

Example 189

7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 1-(bromomethyl)-4-(methylsulfonyl)benzene. MS (ESI): mass calcd. forC₂₅H₂₅FN₂O₄S, 468.15; m/z found, 469.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.02-7.96 (m, 2H), 7.74 (d, J=8.4, 3H), 7.65-7.62 (m, 1H), 7.27-7.20 (m,2H), 5.17 (s, 2H), 4.38-4.34 (m, 2H), 3.87-3.74 (m, 1H), 3.73-3.66 (m,2H), 3.13 (d, J=3.7, 3H), 2.34-2.24 (m, 2H), 2.21-1.98 (m, 3H),1.90-1.80 (m, 1H).

Example 190

4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 4-(bromomethyl)benzonitrile. MS (ESI): mass calcd. for C₂₅H₂₂FN₃O₂,415.17; m/z found, 416.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.80-7.75 (m,2H), 7.72 (d, J=0.8, 1H), 7.69-7.61 (m, 3H), 7.26-7.19 (m, 2H), 5.13 (s,2H), 4.39-4.31 (m, 2H), 3.86-3.74 (m, 1H), 3.72-3.68 (m, 2H), 2.34-2.23(m, 2H), 2.21-1.95 (m, 3H), 1.90-1.80 (m, 1H).

Example 191

7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 1-(bromomethyl)-4-(trifluoromethyl)benzene. MS (ESI): mass calcd.for C₂₅H₂₂F₄N₂O₂, 458.16; m/z found, 459.3 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 7.74-7.61 (m, 6H), 7.26-7.19 (m, 2H), 5.14 (s, 2H), 4.39-4.31(m, 2H), 3.87-3.74 (m, 1H), 3.72-3.68 (m, 2H), 2.33-2.22 (m, 2H),2.19-1.97 (m, 3H), 1.89-1.80 (m, 1H).

Example 192

3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 3-(bromomethyl)benzamide. MS (ESI): mass calcd. for C₂₅H₂₄FN₃O₃,433.18; m/z found, 434.2 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ 8.01-7.97 (m,1H), 7.88-7.83 (m, 1H), 7.74-7.71 (m, 1H), 7.67-7.60 (m, 2H), 7.53-7.47(m, 1H), 7.23-7.19 (m, 2H), 5.14-5.10 (m, 2H), 4.38-4.33 (m, 2H),3.83-3.75 (m, 1H), 3.72-3.67 (m, 2H), 2.32-2.22 (m, 2H), 2.17-2.07 (m,2H), 2.06-1.96 (m, 1H), 1.88-1.80 (m, 1H).

Example 193

4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 4-(bromomethyl)benzamide. MS (ESI): mass calcd. for C₂₅H₂₄FN₃O₃,433.18; m/z found, 434.3 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 7.90 (d,J=8.3, 2H), 7.72 (s, 1H), 7.62 (d, J=5.3, 1H), 7.56 (d, J=8.3, 2H),7.23-7.20 (m, 2H), 5.12 (s, 2H), 4.37-4.34 (m, 2H), 3.82-3.76 (m, 1H),3.72-3.69 (m, 2H), 2.31-2.24 (m, 2H), 2.17-2.11 (m, 2H), 2.06-1.99 (m,1H), 1.88-1.81 (m, 1H).

Example 194

7-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in manner similar to that described inExample 28 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 2-bromo-6-(trifluoromethyl)pyridine. MS (ESI): mass calcd. forC₂₃H₁₉F₄N₃O₂, 445.14; m/z found, 446.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.05 (m, 1H), 7.71 (d, J=1.4, 1H), 7.62-7.59 (m, 1H), 7.51 (d, J=7.4,1H), 7.42 (m, 1H), 7.36-7.30 (m, 2H), 4.37-4.33 (m, 2H), 3.72-3.68 (m,2H), 3.67-3.61 (m, 1H), 2.22-2.09 (m, 4H), 2.03-1.92 (m, 1H), 1.85-1.76(m, 1H).

Example 195

(4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)aceticAcid

A solution of6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol(50 mg, 0.17 mmol) and 2-(4-(bromomethyl)phenyl)acetic acid (38 mg, 0.17mmol) in DMSO (1 mL) was treated with potassium tert-butoxide (38 mg,0.33 mmol) and stirred for 16 hours at 80° Celsius. The reaction wasthen cooled to rt, filtered, and the filtrate subjected directly to HPLCpurification to give(4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acid (8 mg, 9%). MS (ESI): mass calcd. for C₂₆H₂₅FN₂O₄, 448.18; m/zfound, 449.2 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 7.72 (s, 1H), 7.60 (s,1H), 7.40 (d, J=8.1, 2H), 7.31 (d, J=8.1, 2H), 7.19 (d, J=6.0, 2H), 5.04(s, 2H), 4.38-4.32 (m, 2H), 3.78-3.72 (m, 1H), 3.71-3.67 (m, 2H), 3.63(s, 2H), 2.29-2.22 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.97 (m, 1H), 1.84(t, J=9.6, 1H).

Example 196

4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzoicAcid

Prepared in a manner similar to that described in Example 195 byreaction of6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol4-(bromomethyl)benzoic acid. MS (ESI): mass calcd. for C₂₅H₂₃FN₂O₄,434.16; m/z found, 435.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ 8.07-8.03 (m,2H), 7.73 (d, J=1.3, 1H), 7.66-7.64 (m, 1H), 7.57 (d, J=8.4, 2H), 7.22(d, J=4.4, 2H), 5.13 (s, 2H), 4.368-4.35 (m, 2H), 3.83-3.76 (m, 1H),3.74-3.69 (m, 2H), 2.31-2.25 (m, 2H), 2.17-2.09 (m, 2H), 2.06-1.98 (m,1H), 1.88-1.81 (m, 1H).

Example 197

3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine

The title compound was prepared in a manner similar to that described inExample 1 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and3-chloro-7H-pyrrolo[2,3-c]pyridazine. MS (ESI): mass calcd. forC₁₇H₁₆FN₃O, 297.13; m/z found, 298.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ12.05 (s, 1H), 8.15 (d, J=2.2, 1H), 7.80 (d, J=3.4, 1H), 7.71 (m, 1H),7.21 (d, J=8.1, 1H), 6.61 (d, J=3.4, 1H), 3.94 (d, J=1.2, 3H), 2.44-2.35(m, 2H), 2.25-2.14 (m, 2H), 2.13-2.05 (m, 1H), 1.81 (d, J=7.1, 2H).

Example 198

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

A reaction flask containing5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (0.5 g, 2.5 mmol),(4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (0.563 g, 2.51mmol), potassium carbonate (1.041 g, 7.54 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II).CH₂Cl₂(0.093 g, 0.13 mmol) was sealed and the atmosphere exchanged with N₂(3×). The flask was charged with freshly sparged DMF (2 mL), toluene (5mL), and deionized H₂O (5 mL). The mixture was heated for 16 hours at80° Celsius. The reaction mixture was cooled to room temperature,diluted with EtOAc (50 mL) and washed with brine (3×50 mL). The organiclayer was isolated, dried over MgSO₄, filtered, and concentrated todryness. The residue was purified by FCC to give the title compound(0.605 g, 81%). MS (ESI): mass calcd. for C₁₈H₁₉FN₂O, 298.15; m/z found,299.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=0.9 Hz, 1H), 7.44 (s,1H), 7.09-7.01 (m, 2H), 4.62 (s, 1H), 3.89 (d, J=1.3 Hz, 3H), 3.85-3.74(m, 1H), 3.72-3.63 (m, 2H), 3.12 (t, J=8.4 Hz, 2H), 2.41-2.30 (m, 2H),2.22-1.99 (m, 3H), 1.95-1.81 (m, 1H).

Example 199

6-Cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol

Prepared in a manner similar to that described in Example 185 byreaction of5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.MS (ESI): mass calcd. for C₁₇H₁₇FN₂O, 284.13; m/z found, 285.2 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 7.82-7.76 (m, 1H), 7.64 (s, 1H), 7.06 (d,J=8.0, 1H), 6.86 (m, 1H), 3.95 (t, J=8.3, 2H), 3.85-3.72 (m, 1H),3.30-3.22 (m, 2H), 2.41-2.29 (m, 2H), 2.21-1.99 (m, 3H), 1.90-1.81 (m,1H).

Intermediate G

3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenol

Step A

To a 100 mL round-bottomed flask were added a stir bar,2-(1,1-dimethylethyl)-6-fluorophenol (2.62 g, 15.6 mmol),tert-butyldimethylchlorosilane (4.84 g, 31.1 mmol), imidazole (1.46 g,21.5 mmol) and dry DMF (48 mL). The flask was purged with nitrogen andheated at 60° Celsius for 24 hours. The mixture was cooled to roomtemperature and then partitioned between EtOAc and water. The EtOAclayer was washed with water followed by brine. The organic layer wasdried over Na₂SO₄ and concentrated. Purification by FCC yieldedtert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (4.2 g, 96%).¹H NMR (600 MHz, CDCl₃) δ 7.04 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 1.56(s, 6H), 1.39 (s, 9H), 1.01 (d, J=0.7, 9H).

Step B

To a 100 mL round-bottomed flask were added a stir bar, dry THF (15.0mL) and 2,2,6,6-tetramethylpiperidine (2.3 mL, 13.6 mmol). The flask wascooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi inhexanes (5.46 mL, 13.6 mmol) over 2 min. The resultant mixture wasstirred for 5 min and then warmed to 0° Celsius. After 65 min, themixture was re-cooled to −78° Celsius and treated with B(O-iPr)₃ (17.5mL, 13.6 mmol) over 4 min. After 20 min, a solution consisting oftert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (2.57 g, 9.1mmol) and dry THF (5.0 mL) was added over the course of 2 min andstirring continued for 3 hours. The reaction was gradually warmed toroom temperature while stirring for 18 hours, after which time, HOAc(5.2 mL, 91 mmol) was added. The mixture was then poured into water andstirred for 5 min. The aqueous mixture was then extracted with EtOAc(200 mL), the extract dried over Na₂SO₄, filtered and concentrated todryness. Purification by FCC yielded(4-(tert-butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronicacid (2.13 g, 72%).

Step C

(4-(tert-Butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronicacid was coupled to 2-amino-5-bromopyrazine in an analogous manner toStep D in Intermediate A to give the title compound (658 mg, 78%). MS(ESI): mass calcd. for C₁₄H₁₆FN₃O, 261.13; m/z found, 262.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.38 (d, J=3.2, 1H), 8.21 (dd, J=2.3, 1.5, 1H),7.93 (d, J=1.5, 1H), 7.11 (m, 1H), 6.98 (d, J=8.4, 1H), 6.56 (s, 2H),1.32 (s, 9H).

Example 200

5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrazin-2-amine

The title compound was formed as an additional product in the synthesisof Intermediate E in Step C (56 mg 5%) yield. MS (ESI): mass calcd. forC₂₀H₃₀FN₃OSi, 375.21; m/z found, 376.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.47-8.40 (m, 1H), 8.09 (d, J=1.4, 1H), 7.35-7.28 (m, 1H), 7.13 (dd,J=8.5, 1.5, 1H), 4.62 (s, 2H), 1.41 (s, 9H), 1.02 (d, J=0.7, 9H), 0.34(d, J=4.3, 6H).

Example 201

5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating for 4 hours at 120° Celsius and usingIntermediate G. MS (ESI): mass calcd. for C₁₈H₁₈FN₅O, 339.15; m/z found,340.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (d, J=4.8, 2H), 8.22 (s,1H), 8.00 (d, J=1.4, 1H), 7.71-7.62 (m, 1H), 7.35-7.26 (m, 2H), 6.68 (s,2H), 1.30 (s, 9H).

Example 202

6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating for 5 hours at 120° Celsius usingIntermediate G and 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. forC₁₈H₁₉FN₆O, 354.16; m/z found, 355.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.23 (s, 1H), 8.08-7.99 (m, 2H), 7.65 (m, 1H), 7.29 (d, J=8.6, 1H), 6.92(s, 2H), 6.71 (s, 2H), 5.94 (s, 1H), 1.30 (s, 9H).

Example 203

2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating for 15 hours at 140° Celsius usingIntermediate G and 4-amino-2-chloropyrimidine. MS (ESI): mass calcd. forC₁₈H₁₉FN₆O, 354.16; m/z found, 355.0 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.25 (s, 1H), 8.04 (d, J=1.4, 1H), 7.88 (d, J=5.9, 1H), 7.66-7.59 (m,1H), 7.30 (dd, J=8.6, 1.2, 1H), 6.24 (d, J=5.9, 1H), 1.37 (s, 9H).

Example 204

5-{4-tert-Butyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating for 3 hours at 120° Celsius usingIntermediate G and 6-chloro-4-pyrimidinyl methyl ether giving titlecompound and Example 205. MS (ESI): mass calcd. for C₁₉H₂₀FN₅O₂, 369.16;m/z found, 370.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.42 (m, 1H),8.08 (d, J=1.5, 1H), 7.98 (s, 1H), 7.78-7.69 (m, 1H), 7.32-7.27 (m, 1H),5.90 (s, 1H), 4.67 (s, 2H), 3.51 (s, 3H), 1.37 (s, 9H).

Example 205

5-(4-tert-Butyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

Title compound was formed as an additional product from the preparationof Example 204. MS (ESI): mass calcd. for C₁₅H₁₈FN₃O, 275.14; m/z found,276.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.50-8.45 (m, 1H), 8.09 (d,J=1.5, 1H), 7.48-7.40 (m, 1H), 7.17-7.09 (m, 1H), 4.64 (s, 2H), 3.99 (d,J=2.2, 3H), 1.40 (s, 9H).

Intermediate H

3-(2-Aminopyrimidin-5-yl)-6-tert-butyl-2-fluorophenol

The title compound was prepared using conditions similar to thosedescribed Intermediate E using 2-amino-5-bromopyrimidine in Step C. MS(ESI): mass calcd. for C₁₄H₁₆FN₃O, 261.13; m/z found, 262.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 8.39 (d, J=1.5, 2H), 7.02 (dd,J=8.3, 1.3, 1H), 6.89-6.76 (m, 3H), 1.37 (s, 9H).

Example 206

5-(4-tert-Butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrimidin-2-amine

Formed as an additional product during formation of Intermediate F inStep C. MS (ESI): mass calcd. for C₂₀H₃₀FN₃OSi, 375.21; m/z found, 376.0[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.53-8.40 (m, 2H), 7.15-7.08 (m, 1H),6.87-6.77 (m, 1H), 5.22 (s, 2H), 1.41 (s, 9H), 1.01 (s, 9H), 0.33 (d,J=4.2, 6H).

Example 207

5-[4-tert-Butyl-2-fluoro-3-(pyridin-2-yloxy)phenyl]pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 heating at 120° Celsius for 2 hours and usingIntermediate H. MS (ESI): mass calcd. for C₁₈H₁₈FN₅O, 339.15; m/z found,340.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (d, J=4.8, 2H), 8.41 (d,J=1.4, 2H), 7.43-7.35 (m, 1H), 7.35-7.25 (m, 2H), 6.88 (s, 2H), 1.30 (s,9H).

Example 208

5-{3-[(6-Aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating for 15 hours at 140° Celsius usingIntermediate H and 4-amino-6-chloropyrimidine. MS (ESI): mass calcd. forC₁₈H₁₉FN₆O, 354.16; m/z found, 355.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.41 (d, J=1.0, 2H), 8.04 (s, 1H), 7.41-7.32 (m, 1H), 7.27 (d, J=8.4,1H), 6.89 (d, J=4.5, 4H), 5.97-5.89 (m, 1H), 1.30 (s, 9H).

Example 209

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 heating for 13 hours at 140° Celsius usingIntermediate H and 4-amino-2-chloropyrimidine. MS (ESI): mass calcd. forC₁₈H₁₉FN₆O, 354.16; m/z found, 355.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.46 (d, J=1.2, 2H), 8.02 (d, J=5.7, 1H), 7.29-7.24 (m, 1H), 7.18-7.09(m, 1H), 6.12 (d, J=5.7, 1H), 4.98 (s, 2H), 4.80 (s, 2H), 1.40 (s, 9H).

Example 210

5-(4-Bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

Step A: (4-Bromo-2-fluoro-3-methoxyphenyl)boronic Acid

A solution of 2,2,6,6-tetramethylpiperidine TMP (0.98 ml, 5.76 mmol) inTHF (9.8 ml) was cooled to −78° Celsius under N₂. To the solution wasthen added n-BuLi (2.21 N in hexanes, 2.45 mL, 5.41 mmol) slowly overthe course of a couple of min. The mixture was then warmed to 0° Celsiusfor 20-30 min and treated with triisopropyl borate (1.25 ml, 5.41 mmol)was added. After 5 min, 1-bromo-3-fluoro-2-methoxybenzene (1.0 g, 4.9mmol) was slowly added and the reaction was stirred at −78° Celsius.After 1.5 hours, the resulting mixture was warmed to room temperaturewith AcOH (2.8 ml, 49 mmol), poured into water, and extracted withEtOAc. The organic extract was isolated, dried over MgSO₄, filtered andconcentrated to dryness to yield(5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-yl)boronic acid as asolid (940 mg, 77%) that was used without further purification.

Step B

A mixture of the crude (4-bromo-2-fluoro-3-methoxyphenyl)boronic acid(940 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (1.31 g, 7.56 mmol) wastreated with EtOH (12.4 ml) and toluene (12.8 ml) The resultingsuspension was then treated with aqueous Na₂CO₃ (2.0 N, 9.44 ml, 18.9mmol). The resulting mixture was then sparged with nitrogen for 10 min,before adding Pd(PPh₃)₄ (218 mg, 0.189 mmol) and heating at 80° Celsiusfor 17 hours. The reaction was cooled to room temperature andpartitioned between saturated NH₄Cl and EtOAc. The organic layer wasdried over MgSO₄ and concentrated to dryness. The residue was suspendedin DCM was and the resultant solid isolated by filtration to afford thetitle compound (300 mg, 27%), which was used without furtherpurification. Additional product was obtained by concentrating the DCMlayer and subjecting the residue to FCC to afford the title compound(560 mg, 50%). MS (ESI): mass calcd. for C₁₁H₉BrFN₃O, 296.99; m/z found,298.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.34 (dd, J=2.6, 1.5, 1H),8.00 (d, J=1.5, 1H), 7.54-7.49 (m, 2H), 6.78 (s, 2H), 3.90 (d, J=0.6,3H).

Example 211

5-(4-Cyclopentyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

A microwave vial was charged with5-(4-bromo-2-fluoro-3-methoxyphenyl)-pyrazin-2-amine (50 mg, 0.17 mmol),palladium acetate (2.9 mg, 0.013 mmol) and2-dicyclohexylphosphine-2′,6′-dimethoxy-1,1′-biphenyl (7.7 mg, 0.018mmol). The vial was evacuated and back filled with nitrogen.Cyclopentylzinc bromide (0.5 M in THF, 0.67 ml, 0.34 mmol) was thenadded and the mixture heated at 70° Celsius for 19 hours. The reactionwas cooled to rt and the mixture subjected to HPLC purification toafford the title compound (7 mg, 15%). MS (ESI): mass calcd. forC₁₆H₁₈FN₃O, 287.14; m/z found, 288.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.50-8.46 (m, 1H), 8.09 (d, J=1.5, 1H), 7.54-7.48 (m, 1H), 7.09 (dd,J=8.3, 1.1, 1H), 4.65 (s, 2H), 3.94 (d, J=1.2, 3H), 3.42-3.33 (m, 1H),2.11-1.99 (m, 2H), 1.88-1.78 (m, 2H), 1.77-1.66 (m, 2H), 1.59-1.53 (m,2H).

Example 212

5-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 83 using cyclopentylzinc bromide (0.5 M solution in THF). MS(ESI): mass calcd. for C₂₂H₂₂FN₃O, 363.17; m/z found, 364.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 8.10 (s, 1H), 7.58-7.51 (m, 1H),7.51-7.45 (m, 2H), 7.43-7.32 (m, 3H), 7.10 (dd, J=8.3, 1.1, 1H), 5.09(s, 2H), 4.66 (s, 2H), 3.43-3.31 (m, 1H), 2.00-1.89 (m, 2H), 1.84-1.72(m, 2H), 1.71-1.47 (m, 4H).

Example 213

5-[4-Cyclopentyl-2-fluoro-3-(1-methylethoxy)phenyl]pyrazin-2-amine

Step A

5-(4-Chloro-2-fluoro-3-isopropoxyphenyl)pyrazin-2-amine was preparedusing procedures similar to those described in Example 216 utilizing4-chloro-2-fluoro-3-isopropoxyphenylboronic acid. MS (ESI): mass calcd.for C₁₃H₁₃ClFN₃O, 281.07; m/z found, 282.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.32 (d, J=3.6, 2H), 7.60 (m, 1H), 7.31-7.22 (m, 1H), 4.52 (m,1H), 1.41-1.38 (m, 6H).

Step B

The title compound was prepared using analogous conditions described inExample 83 using 5-(4-chloro-3-isopropoxyphenyl)pyrazin-2-amine andcyclopentylzinc bromide (0.5 M solution in THF). MS (ESI): mass calcd.for C₁₈H₂₂FN₃O, 315.17; m/z found, 316.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃)δ 8.48-8.45 (m, 1H), 8.08 (d, J=1.5, 1H), 7.52-7.46 (m, 1H), 7.10 (dd,J=8.3, 1.2, 1H), 4.64 (s, 2H), 4.48-4.38 (m, 1H), 3.49-3.40 (m, 1H),2.10-2.01 (m, 2H), 1.88-1.79 (m, 2H), 1.75-1.67 (m, 2H), 1.58-1.48 (m,3H), 1.35 (dd, J=6.1, 0.6, 6H).

Example 214

2-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine

Step A

2-(3-(Benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine] wasprepared using procedures similar to those described in Example 216utilizing 5-bromo-4,7-diazaindole. MS (ESI): mass calcd. forC₁₉H₁₃ClFN₃O, 353.07; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ9.35 (s, 1H), 8.70 (d, J=2.9, 1H), 7.72-7.65 (m, 2H), 7.58-7.51 (m, 2H),7.44-7.30 (m, 4H), 6.82 (dd, J=3.7, 1.9, 1H), 5.20 (s, 2H).

Step B

The title compound was prepared using analogous conditions described inExample 83 using2-(3-(benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine andcyclopentylzinc bromide (0.5 M solution in THF). MS (ESI): mass calcd.for C₂₄H₂₂FN₃O, 387.1747; m/z found, 388.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 9.26 (s, 1H), 8.73 (d, J=2.8, 1H), 7.69-7.61 (m, 2H), 7.50 (dd,J=8.1, 6.5, 2H), 7.43-7.32 (m, 3H), 7.16 (dd, J=8.3, 1.1, 1H), 6.82 (dd,J=3.7, 1.9, 1H), 5.12 (s, 2H), 3.46-3.33 (m, 1H), 2.04-1.91 (m, 2H),1.87-1.75 (m, 2H), 1.73-1.49 (m, 4H).

Example 215

5-[3-(Benzyloxy)-4-tert-butylphenyl]pyrazin-2-amine

Step A: 2-(Benzyloxy)-4-bromo-1-(tert-butyl)benzene

5-Bromo-2-tert-butylphenol (1.08 g, 4.71 mmol), benzyl bromide (0.69 mL,5.7 mmol) and Cs₂CO₃ (2.3 g, 7.1 mmol) were added to 23.6 mL ofacetonitrile and stirred at room temperature for 64 hours. The reactionmixture was filtered and concentrated to dryness. Purification by FCCresulted in title compound (1.39 g, 92%).

Step B:2-(3-(Benzyloxy)-4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

2-(Benzyloxy)-4-bromo-1-(tert-butyl)benzene (495 mg, 1.55 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (482 mg,1.86 mmol) were dissolved in 1,4-dioxane (10.3 mL) and treated with KOAc(461 mg, 4.65 mmol). The solution was sparged with N₂ andtris((E,E)-dibenzylideneacetone)dipalladium (42 mg, 0.047 mmol) andtricyclohexylphosphine (30 mg, 0.11 mmol) were added. The mixture washeated at 100° Celsius for 4 hours. The reaction mixture was filteredthrough anhydrous NaSO₄ and a plug of diatomacious earth, then subjectedto FCC to give title compound (138 mg, 24%).

Step C

2-Amino-5-bromopyrazine (65 mg, 0.38 mmol) and2-(3-(benzyloxy)-4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,(138 mg, 0.38 mmol) were partially dissolved in DME (2.5 mL) and treatedwith of 2.0 M aqueous K₂CO₃ (0.83 mL). The solution was sparged andtreated with Pd(dppf)Cl₂.CH₂Cl₂ (30 mg, 0.038 mmol). The mixture wasstirred at room temperature for 64 hours. The mixture was dried,filtered through a pad of diatomacious earth and then subjected to FCCfollowed by HPLC to give the title compound (4 mg, 2%). MS (ESI): masscalcd. for C₂₁H₂₃N₃O, 333.18; m/z found, 334.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.30 (d, J=1.4, 1H), 8.18 (d, J=1.4, 1H), 7.56-7.48 (m, 3H),7.45-7.32 (m, 6H), 5.21 (s, 2H), 1.42 (s, 10H).

Example 216

5-[3-(Benzyloxy)-4-chloro-2-fluorophenyl]pyrazin-2-amine

2-Amino-5-bromopyrazine (100 mg, 0.57 mmol) and3-benzyloxy-4-chloro-2-fluorophenylboronic acid, (193 mg, 0.57 mmol)were partially dissolved in DME (2.5 mL) and treated with 2.0 M aqueousK₂CO₃ (0.83 mL). The solution was sparged and treated withPd(dppf)Cl₂.CH₂Cl₂ (47 mg, 0.057 mmol). The mixture was stirred at roomtemperature for 18 hours. The mixture was dried, filtered through a padof diatomacious earth and then subjected to FCC to give the titlecompound (146 mg, 77%). MS (ESI): mass calcd. for C₁₇H₁₃ClFN₃O, 329.07;m/z found, 330.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (dd, J=2.4, 1.6,1H), 8.06 (d, J=1.5, 1H), 7.61-7.50 (m, 3H), 7.43-7.31 (m, 3H), 7.24(dd, J=8.9, 1.9, 1H), 5.16 (s, 2H), 4.78 (s, 2H).

Example 217

5-[3-(Benzyloxy)-4-cyclobutylphenyl]pyrazin-2-amine

Step A

5-(3-Benzyloxy)-4-chlorophenyl)pyrazin-2-amine was prepared usingprocedures similar to those described in Example 216 utilizing(3-(benzyloxy)-4-chlorophenyl)-boronic acid. MS (ESI): mass calcd. forC₁₇H₁₄ClN₃O, 311.08; m/z found, 312.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.38 (d, J=1.4, 1H), 8.03 (d, J=1.5, 1H), 7.59 (d, J=1.9, 1H), 7.55-7.48(m, 2H), 7.47-7.36 (m, 4H), 7.33 (t, J=7.4, 1H), 5.24 (s, 2H), 4.69 (s,2H).

Step B

The title compound was prepared using analogous conditions described inExample 83 using 5-(3-(benzyloxy)-4-chlorophenyl)pyrazin-2-amine. MS(ESI): mass calcd. for C₂₁H₂₁N₃O, 331.17; m/z found, 332.4 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.42 (d, J=1.5, 1H), 8.06 (d, J=1.5, 1H),7.50-7.45 (m, 3H), 7.45-7.37 (m, 3H), 7.36-7.28 (m, 2H), 5.15 (s, 2H),4.60 (s, 2H), 3.88-3.78 (m, 1H), 2.41-2.30 (m, 2H), 2.23-2.10 (m, 2H),2.09-1.95 (m, 1H), 1.88-1.78 (m, 1H).

Example 218

3-amino-6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 198 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acidand 3-amino-6-bromopyrazine-2-carbonitrile. MS (ESI): mass calcd. forC₁₆H₁₅FN₄O₂, 298.12; m/z found, 299.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.62-8.61 (m, 1H), 7.54-7.46 (m, 1H), 7.21-7.15 (m, 1H), 3.89-3.88 (m,3H), 3.86-3.79 (m, 1H), 2.41-2.32 (m, 2H), 2.24-2.04 (m, 3H), 1.94-1.85(m, 1H).

Example 219

6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described inExample 198 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acidand 6-chloropyridazin-3-amine. MS (ESI): mass calcd. for C₁₅H₁₆FN₃O,273.13; m/z found, 274.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.73-7.62 (m,2H), 7.17-7.14 (m, 1H), 6.84-6.78 (m, 1H), 3.92-3.87 (m, 3H), 3.86-3.77(m, 1H), 2.42-2.32 (m, 2H), 2.23-1.98 (m, 3H), 1.93-1.83 (m, 1H).

Example 220

6-Cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The title compound was prepared in a manner similar to that described inExample 185 by reaction of Intermediate I. MS (ESI): mass calcd. forC₁₇H₁₅FN₂O, 282.12; m/z found, 283.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.90-8.83 (m, 1H), 8.63-8.56 (m, 1H), 7.82-7.75 (m, 1H), 7.18-7.12 (m,1H), 7.08-7.01 (m, 1H), 6.98-6.93 (m, 1H), 3.91-3.76 (m, 1H), 2.45-2.34(m, 2H), 2.25-2.14 (m, 2H), 2.11-2.02 (m, 1H), 1.95-1.85 (m, 1H).

Example 221

6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol

The title compound was prepared in a manner similar to that described inExample 185 by reaction of3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine.MS (ESI): mass calcd. for C₁₆H₁₄FN₃O, 283.11; m/z found, 284.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.69-8.65 (m, 1H), 8.57-8.51 (m, 1H),7.31-7.27 (m, 1H), 7.21-7.16 (m, 1H), 7.10-7.05 (m, 1H), 3.95-3.82 (m,1H), 2.46-2.38 (m, 2H), 2.26-2.07 (m, 3H), 1.95-1.86 (m, 1H).

Example 222

3-Amino-6-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 185 by reaction of3-amino-6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-pyrazine-2-carbonitrile.MS (ESI): mass calcd. for C₁₅H₁₃FN₄O, 284.11; m/z found, 285.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.63-8.58 (m, 1H), 7.27-7.20 (m, 1H),7.11-7.05 (m, 1H), 3.89-3.74 (m, 1H), 2.42-2.31 (m, 2H), 2.24-1.99 (m,3H), 1.92-1.81 (m, 1H).

Example 223

3-(6-Aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol

The title compound was prepared in a manner similar to that described inExample 185 by reaction of6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine. MS (ESI):mass calcd. for C₁₄H₁₄FN₃O, 259.11; m/z found, 260.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.15-8.08 (m, 1H), 7.57-7.50 (m, 1H), 7.22-7.16 (m, 1H),7.15-7.10 (m, 1H), 3.89-3.76 (m, 1H), 2.42-2.33 (m, 2H), 2.22-2.00 (m,3H), 1.92-1.82 (m, 1H).

Example 224

5,5′-((Pyrimidine-2,4-diylbis(oxy))bis(4-cyclobutyl-2-fluoro-3,1-phenylene))bis(pyrazin-2-amine)

The title compound was prepared in a manner similar to that described inExample 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-4-(methylsulfonyl)pyrimidine. MS (ESI): mass calcd. forC₃₂H₂₈F₂N₈O₂, 594.23; m/z found, 595.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.50 (d, J=5.7, 1H), 8.36 (d, J=4.4, 2H), 7.95 (d, J=8.4, 2H), 7.61-7.52(m, 2H), 7.06-6.99 (m, 2H), 6.81 (d, J=5.6, 1H), 3.61-3.41 (m, 2H),2.20-1.89 (m, 1 OH), 1.78 (d, J=12.3, 2H).

Example 225

7-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described inExample 69 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 2-chloropyrimidine. MS (ESI): mass calcd. for C₂₁H₁₉FN₄O₂, 378.15;m/z found, 379.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.63-8.58 (m, 2H),7.75-7.71 (m, 1H), 7.66-7.62 (m, 1H), 7.46-7.39 (m, 1H), 7.34-7.28 (m,1H), 7.28-7.23 (m, 1H), 4.39-4.33 (m, 2H), 3.73-3.59 (m, 3H), 2.24-2.08(m, 4H), 2.04-1.93 (m, 1H), 1.87-1.76 (m, 1H).

Example 226

2-(6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 69 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 2-chloro-4-aminopyrimidine. MS (ESI): mass calcd. for C₂₁H₂₀FN₅O₂,393.16; m/z found, 394.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.05-8.00 (m,1H), 7.76-7.72 (m, 1H), 7.64-7.61 (m, 1H), 7.51-7.45 (m, 1H), 7.36-7.31(m, 1H), 6.50-6.45 (m, 1H), 4.39-4.33 (m, 2H), 3.74-3.64 (m, 3H),2.33-2.23 (m, 2H), 2.23-2.14 (m, 2H), 2.11-2.01 (m, 1H), 1.91-1.83 (m,1H).

Example 227

7-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine

The title compound was prepared in a manner similar to that described inExample 69 using6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoland 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₂₂H₂₁FN₄O₃,408.16; m/z found, 409.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.35-8.30 (m,1H), 7.75-7.71 (m, 1H), 7.66-7.61 (m, 1H), 7.46-7.39 (m, 1H), 7.34-7.27(m, 1H), 6.44-6.39 (m, 1H), 4.40-4.31 (m, 2H), 4.05-3.97 (m, 3H),3.74-3.67 (m, 2H), 3.67-3.54 (m, 1H), 2.28-2.09 (m, 4H), 2.06-1.93 (m,1H), 1.87-1.78 (m, 1H).

Example 228

5-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl-1H-pyrrolo[2,3-I]pyridine

The title compound was prepared in a manner similar to that described inExample 69 using6-cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol and4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₂₂H₁₉FN₄O₂,390.15; m/z found, 391.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.51-8.44 (m,2H), 8.38-8.33 (m, 1H), 7.61-7.56 (m, 1H), 7.54-7.47 (m, 1H), 7.38-7.31(m, 1H), 6.77-6.71 (m, 1H), 6.45-6.39 (m, 1H), 4.03-3.98 (m, 3H),3.70-3.59 (m, 1H), 2.28-2.13 (m, 4H), 2.08-1.96 (m, 1H), 1.89-1.79 (m,1H).

Example 229

2-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared in a manner similar to that described inExample 69 using6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol and4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₂₁H₁₈FN₅O₂,391.14; m/z found, 392.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.61-8.57 (m,1H), 8.38-8.34 (m, 1H), 7.87-7.84 (m, 1H), 7.83-7.77 (m, 1H), 7.40-7.35(m, 1H), 6.74-6.69 (m, 1H), 6.43-6.40 (m, 1H), 4.03-3.98 (m, 3H),3.71-3.60 (m, 1H), 2.26-2.15 (m, 4H), 2.08-1.97 (m, 1H), 1.89-1.81 (m,1H).

Example 230

2-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine

The title compound was prepared in a manner similar to that described inExample 69 using6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol and2-chloropyrimidine. MS (ESI): mass calcd. for C₂₀H₁₆FN₅O, 361.13; m/zfound, 362.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.65-8.61 (m, 2H),8.60-8.56 (m, 1H), 7.86-7.83 (m, 1H), 7.82-7.76 (m, 1H), 7.39-7.35 (m,1H), 7.28-7.23 (m, 1H), 6.74-6.69 (m, 1H), 3.75-3.64 (m, 1H), 2.26-2.15(m, 4H), 2.06-1.95 (m, 1H), 1.88-1.78 (m, 1H).

Example 231

6-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoland 2-chloropyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13;m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.64-8.59 (m, 2H),8.16-8.10 (m, 1H), 7.76-7.70 (m, 1H), 7.58-7.53 (m, 1H), 7.39-7.34 (m,1H), 7.29-7.24 (m, 1H), 3.74-3.62 (m, 1H), 2.26-2.09 (m, 4H), 2.06-1.94(m, 1H), 1.87-1.77 (m, 1H).

Example 232

6-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described inExample 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoland 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₉H₁₈FN₅O₂,367.14; m/z found, 368.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.29-8.26 (m,1H), 8.15-8.10 (m, 1H), 7.76-7.70 (m, 1H), 7.57-7.53 (m, 1H), 7.39-7.35(m, 1H), 5.84-5.81 (m, 1H), 3.74-3.61 (m, 1H), 3.53-3.47 (m, 3H),2.35-2.24 (m, 2H), 2.23-2.14 (m, 2H), 2.10-1.99 (m, 1H), 1.90-1.81 (m,1H).

Example 233

6-(3-(6-Aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidin-4-ol

The title compound was prepared in a manner similar to that described inExample 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoland 4-chloro-6-methoxypyrimidine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O₂,353.13; m/z found, 354.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.15-8.11 (m,1H), 8.08-8.05 (m, 1H), 7.76-7.71 (m, 1H), 7.57-7.52 (m, 1H), 7.41-7.35(m, 1H), 5.81-5.76 (m, 1H), 3.74-3.63 (m, 1H), 2.34-2.24 (m, 2H),2.24-2.14 (m, 2H), 2.10-2.01 (m, 1H), 1.91-1.82 (m, 1H).

Example 234

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2-carbonitrile

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-chloropyrimidine-2-carbonitrile. ¹H NMR (400 MHz, CD₃OD) δ 8.99 (s,1H), 8.76-8.72 (m, 1H), 8.53 (d, J=6.1, 1H), 8.00 (d, J=6.1, 1H),7.38-7.30 (m, 1H), 7.12 (d, J=8.1, 1H), 3.89-3.77 (m, 1H), 2.42-2.32 (m,2H), 2.24-2.14 (m, 2H), 2.11-2.00 (m, 1H), 1.92-1.83 (m, 1H).

Example 235

6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,2-trimethylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and6-chloro-N,N,2-trimethylpyrimidin-4-amine. MS (ESI): mass calcd. forC₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.30-8.25 (m, 1H), 8.11 (d, J=1.5, 1H), 7.89-7.82 (m, 1H), 7.38 (d,J=8.0, 1H), 5.74 (s, 1H), 3.71-3.61 (m, 1H), 3.17 (s, 6H), 2.53 (s, 3H),2.34-2.18 (m, 4H), 2.13-2.00 (m, 1H), 1.94-1.83 (m, 1H).

Example 236

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy-N,N,6-trimethylpyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-chloro-N,N,6-trimethylpyrimidin-2-amine. MS (ESI): mass calcd. forC₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.25-8.22 (m, 1H), 8.12 (d, J=1.5, 1H), 7.82 (t, J=7.9, 1H), 7.33 (d,J=8.3, 1H), 6.65 (d, J=0.7, 1H), 3.67-3.57 (m, 1H), 3.19-2.95 (m, 5H),2.56 (d, J=0.6, 3H), 2.30-2.15 (m, 4H), 2.08-1.99 (m, 1H), 1.91-1.81 (m,1H).

Example 237

6-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N-dimethylpyrimidin-4-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and6-chloro-N,N-dimethylpyrimidin-4-amine. MS (ESI): mass calcd. forC₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.26 (d, J=1.4, 1H), 8.23-8.18 (m, 2H), 7.86-7.79 (m, 1H), 7.32 (d,J=8.1, 1H), 6.11 (d, J=0.6, 1H), 3.70-3.59 (m, 1H), 3.14 (d, J=10.6,6H), 2.29-2.14 (m, 4H), 2.08-1.95 (m, 1H), 1.90-1.80 (m, 1H).

Example 238

Ethyl5-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol andethyl 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate.MS (ESI): mass calcd. for C₂₂H₂₁F₄N₅O₃, 479.16; m/z found, 480.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J=1.4, 1H), 8.11 (d, J=1.6, 1H),7.71-7.64 (m, 1H), 7.32 (d, J=8.3, 1H), 3.99-3.86 (m, 6H), 2.42-2.23 (m,4H), 2.16-2.05 (m, 1H), 1.96-1.87 (m, 1H), 0.98 (t, J=7.1, 3H).

Example 239

5-(4-Cyclobutyl-2-fluoro-3-((5-(methylsulfonyl)pyridin-2-yl)oxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and2-chloro-5-(methylsulfonyl)pyridine. MS (ESI): mass calcd. forC₂₀H₁₉FN₄O₃S, 414.12; m/z found, 415.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.61-8.59 (m, 1H), 8.37-8.33 (m, 1H), 8.25 (d, J=1.4, 1H), 8.19 (s, 1H),7.85-7.78 (m, 1H), 7.33-7.29 (m, 2H), 3.68-3.56 (m, 1H), 3.18 (s, 3H),2.23-2.12 (m, 4H), 2.04-1.93 (m, 1H), 1.86-1.77 (m, 1H).

Example 240

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-(tert-butyl)pyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-(tert-butyl)-6-chloropyrimidin-2-amine. MS (ESI): mass calcd. forC₂₂H₂₅FN₆O, 408.21; m/z found, 409.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.27-8.23 (m, 1H), 8.10 (d, J=1.5, 1H), 7.79 (t, J=7.9, 1H), 7.31 (d,J=8.2, 1H), 6.76 (s, 1H), 3.69-3.59 (m, 1H), 2.30-2.15 (m, 4H),2.09-1.98 (m, 1H), 1.91-1.82 (m, 1H), 1.44 (s, 9H).

Example 241

5-(3-((4-(1,5-Dioxa-9-azaspiro[5.5]undecan-9-yl)pyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and9-(2-chloropyrimidin-4-yl)-1,5-dioxa-9-azaspiro[5.5]undecane. MS (ESI):mass calcd. for C₂₆H₂₉FN₆O₃, 492.23; m/z found, 493.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD) δ 8.25 (s, 1H), 8.16 (s, 1H), 8.11 (d, J=7.4, 1H), 7.86(t, J=7.9, 1H), 7.36 (d, J=8.3, 1H), 6.89-6.86 (m, 1H), 3.87 (t, J=5.5,4H), 3.74-3.57 (m, 5H), 2.35-2.16 (m, 4H), 2.12-2.02 (m, 1H), 1.96-1.63(m, 7H).

Example 242

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isobutylpyrimidin-2-amine

The title compound was prepared in a manner similar to that described inExample 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and4-chloro-6-isobutylpyrimidin-2-amine. MS (ESI): mass calcd. forC₂₂H₂₅FN₆O, 408.21; m/z found, 409.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.26 (s, 1H), 8.07 (d, J=1.4, 1H), 7.77 (t, J=7.9, 1H), 7.28 (d, J=8.3,1H), 6.66 (s, 1H), 3.68-3.57 (m, 1H), 2.65 (d, J=7.4, 2H), 2.30-2.23 (m,2H), 2.21-2.15 (m, 2H), 2.13-2.08 (m, 1H), 2.07-2.01 (m, 1H), 1.91-1.83(m, 1H), 1.05 (d, J=6.6, 6H).

Intermediate I

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine

To a 5 mL microwave vial were added a stir bar, 5-bromo-7-azaindole (59mg, 0.30 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (74mg, 0.33 mmol), 14.7 mg Pd(dppf)Cl₂.CH₂Cl₂ (15 mg, 0.18 mmol) and K₂CO₃(129 mg, 0.93 mmol). The vial was flushed with nitrogen and then chargedwith sparged toluene (0.50 mL), sparged water (0.50 mL) and sparged DMF(0.30 mL). The vial was heated at 80° Celsius for 24 hours beforecooling to room temperature, diluting the reaction mixture with DCM,drying the mixture over MgSO₄ filtering through a plug of diatomaciousearth and concentrating to dryness. The dark residue was subjected toFCC to give the title compound as a white solid (67 mg, 76%). MS (ESI):mass calcd. for C₁₈H₁₇N₂FO 296.13, m/z found 297.1 [M+H]⁺. ¹H NMR (600MHz, CDCl₃) δ 9.88 (s, 1H), 8.52-8.46 (m, 1H), 8.13-8.09 (m, 1H),7.42-7.37 (dd, J=3.5, 2.3, 1H), 7.21-7.16 (m, 1H), 7.16-7.11 (m, 1H),6.59-6.54 (dd, J=3.5, 1.9, 1H), 3.93 (s, 3H), 3.89-3.79 (m, 1H),2.43-2.34 (m, 2H), 2.24-2.14 (m, 2H), 2.13-2.02 (m, 1H), 1.93-1.85 (m,1H).

Example 243

N-(2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide

A mixture of N-(2-chloroethyl)methanesulfonamide (146 mg, 0.93 mmol),3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (200 mg, 0.77 mmol),Cs₂CO₃ (376 mg, 1.16 mmol) and DMF (6 mL) was stirred at roomtemperature for 16 hours, and then treated with water (10 mL). Themixture was extracted with EtOAc (3×20 ml). The combined organic phaseswere dried, concentrated to dryness, and the residue purified using FCCto give the title compound (165 mg, 56%). MS (CI): mass calcd. forC₂₁H₂₁FN₄O₃S, 380.13; m/z found, 381.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.43 (s, 1H), 8.08 (s, 1H), 7.55 (m, 1H), 7.15 (d, J=8.2 Hz, 1H),5.44-5.26 (m, 1H), 4.78 (s, 2H), 4.10 (t, J=4.9 Hz, 2H), 3.84-3.69 (m,1H), 3.60-3.49 (m, 2H), 3.05 (s, 3H), 2.42-2.27 (m, 2H), 2.22-2.01 (m,3H), 1.94-1.80 (m, 1H).

Example 244

5-(4-Cyclobutyl-2-fluoro-3-(2-morpholinoethoxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 243 using 4-(2-bromoethyl)morpholine. MS (CI): mass calcd. forC₂₀H₂₅FN₄O₂, 372.20; m/z found, 373.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.51-8.42 (m, 1H), 8.09 (d, J=1.4, 1H), 7.54 (m, 1H), 7.15 (d, J=8.2,1H), 4.74 (s, 2H), 4.18 (t, J=5.3, 2H), 3.84 (dd, J=18.0, 6.6, 5H), 2.89(s, 2H), 2.70 (s, 4H), 2.39-2.32 (m, 2H), 2.20-2.12 (m, 2H), 2.08-2.01(m, 1H), 1.88 (d, J=10.4, 1H).

Example 245

Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate

The title compound was prepared using analogous conditions described inExample 243 using ethyl 4-bromobutanoate. MS (CI): mass calcd. forC₂₀H₂₄FN₃O₃, 373.18; m/z found, 374.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.52-8.38 (m, 1H), 8.08 (d, J=1.6, 1H), 7.53 (m, 1H), 7.14 (d, J=8.2,1H), 4.65 (s, 2H), 4.17 (q, J=7.2, 2H), 4.04 (t, J=6.2, 2H), 3.86-3.75(m, 1H), 2.59 (t, J=7.4, 2H), 2.39-2.30 (m, 2H), 2.20-2.03 (m, 5H), 1.87(ddd, J=11.3, 10.3, 8.7, 1H), 1.28 (t, J=7.1, 3H).

Example 246

tert-Butyl3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)azetidine-1-carboxylate

The title compound was prepared using analogous conditions described inExample 243 using tert-butyl3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate. MS (CI): masscalcd. for C₂₃H₂₉FN₄O₃, 428.22; m/z found, 429.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.45 (s, 1H), 8.09 (d, J=1.2, 1H), 7.54 (m, 1H), 7.15 (d,J=8.2, 1H), 4.70 (s, 2H), 4.16 (d, J=6.5, 2H), 4.09 (t, J=8.5, 2H),3.90-3.83 (m, 2H), 3.82-3.73 (m, 1H), 3.04-2.92 (m, 1H), 2.40-2.28 (m,2H), 2.21-2.01 (m, 3H), 1.92-1.83 (m, 1H), 1.45 (s, 9H).

Example 247

tert-Butyl3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared using analogous conditions described inExample 243 using tert-butyl3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate. MS (CI): masscalcd. for C₂₄H₃₁FN₄O₃, 442.24; m/z found, 465.2 [M+Na]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.48-8.43 (m, 1H), 8.09 (d, J=1.5, 1H), 7.53 (m, 1H), 7.14(d, J=8.3, 1H), 4.65 (s, 2H), 4.04-3.91 (m, 2H), 3.86-3.75 (m, 1H),3.69-3.34 (m, 3H), 3.29-3.25 (m, 1H), 2.71-2.63 (m, 1H), 2.38-2.31 (m,2H), 2.19-2.03 (m, 4H), 1.92-1.76 (m, 2H), 1.48 (s, 9H).

Example 248

tert-Butyl2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

The title compound was prepared using analogous conditions described inExample 243 using tert-butyl2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate. MS (CI): masscalcd. for C₂₄H₃₁FN₄O₃, 442.24; m/z found, 443.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.46 (s, 1H), 8.08 (s, 1H), 7.55 (s, 1H), 7.13 (s, 1H),4.64 (s, 2H), 4.09 (s, 2H), 3.85-3.77 (m, 2H), 3.42 (s, 2H), 2.39-2.25(m, 3H), 2.18-1.98 (m, 5H), 1.92-1.81 (m, 2H), 1.44 (s, 9H).

Example 249

tert-Butyl3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)piperidine-1-carboxylate

The title compound was prepared using analogous conditions described inExample 243 using tert-butyl 2-(bromomethyl)piperidine-1-carboxylate. MS(CI): mass calcd. for C₂₅H₃₃FN₄O₃, 456.25; m/z found, 457.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.45 (m, 1H), 8.09 (m, 1H), 7.52 (m, 1H), 7.14(d, J=8.2, 1H), 4.63 (s, 2H), 4.30-4.18 (m, 1H), 4.04-3.93 (m, 1H),3.91-3.85 (m, 2H), 3.83-3.75 (m, 1H), 2.88-2.72 (m, 2H), 2.41-2.30 (m,2H), 2.24-1.96 (m, 5H), 1.95-1.80 (m, 2H), 1.76-1.67 (m, 1H), 1.57-1.50(m, 1H), 1.48 (s, 9H).

Example 250

2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethanol

The title compound was prepared using analogous conditions described inExample 243 using 2-(2-bromoethoxy)tetrahydro-2H-pyran. The initialalkylation product was treated with a 0.2 M methanolic HCl, and theresulting mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated and the residue was subjected to FCCto obtain the titled compound. MS (CI): mass calcd. for C₁₆H₁₈FN₃O₂,303.14; m/z found, 304.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (d,J=1.6, 1H), 7.99 (d, J=1.4, 1H), 7.50 (t, J=7.9, 1H), 7.20 (d, J=8.2,1H), 6.64 (s, 2H), 4.86 (t, J=5.5, 1H), 3.98 (t, J=5.0, 2H), 3.85 (dd,J=17.8, 8.8, 1H), 3.70 (dd, J=10.4, 5.2, 2H), 2.30 (ddd, J=13.8, 8.3,5.8, 2H), 2.14-2.05 (m, 2H), 2.02-1.95 (m, 1H), 1.82 (dd, J=18.6, 9.3,1H).

Example 251

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoic acid

Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate(300 mg, 0.8 mmol) was dissolved in THF (6 ml), then a solution ofLiOH.H2O (101 mg, 2.41 mmol) and water (2 ml) was added. The reactionwas stirred overnight, then the mixture was acidified to pH=7 by adding1M HCl. The mixture was concentrated to dryness and subjected to FCC togive the title compound (135 mg. 45%). MS (CI): mass calcd. forC₁₈H₂₀FN₃O₃, 345.15; m/z found, 346.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 12.22 (s, 1H), 8.38-8.29 (m, 1H), 8.05 (d, J=1.6, 1H), 7.56 (m, 1H),7.26 (d, J=8.2, 1H), 6.70 (s, 2H), 4.02 (t, J=6.4, 2H), 3.87-3.77 (m,1H), 2.50 (t, J=7.3, 2H), 2.40-2.30 (m, 2H), 2.20-1.99 (m, 5H),1.92-1.83 (m, 1H).

Example 252

5-(4-Cyclobutyl-2-fluoro-3-((tetrahydrofuran-2-yl)methoxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 243 using 2-(bromomethyl)tetrahydro-[2H]-pyran at 60° Celsius.MS (CI): mass calcd. for C₁₉H₂₂FN₃O₂, 343.17; m/z found, 344.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.56-8.37 (m, 1H), 8.08 (d, J=1.5, 1H), 7.53(dd, J=10.2, 5.4, 1H), 7.15 (d, J=8.3, 1H), 4.62 (s, 2H), 4.34-4.21 (m,1H), 4.08-4.03 (m, 1H), 4.00-3.81 (m, 4H), 2.41-2.32 (m, 2H), 2.17-1.82(m, 8H).

Example 253

racemic1-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)propan-2-ol

Step A:5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 243 heating at 60° Celsius using (rac)-epichlorohydrin. ¹H NMR(400 MHz, CDCl₃) δ 8.57-8.40 (m, 1H), 8.08 (d, J=1.5, 1H), 7.54 (dd,J=14.2, 6.6, 1H), 7.15 (d, J=8.2, 1H), 4.64 (s, 2H), 4.28 (dd, J=11.2,3.2, 1H), 3.98 (dd, J=11.2, 6.1, 1H), 3.92-3.81 (m, 1H), 3.38 (td,J=6.4, 3.2, 1H), 2.92-2.86 (m, 1H), 2.72 (dd, J=5.0, 2.6, 1H), 2.43-2.34(m, 2H), 2.20-2.01 (m, 3H), 1.93-1.83 (m, 1H).

Step B:1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)-propan-2-ol

A mixture of5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine(150 mg, 0.48 mmol), isobutylamine (105 mg, 1.43 mmol) and MeOH (5 mL)was heated in sealed tube to 60° Celsius for 5 hours, then the solventwas removed. The residue was subjected to FCC to give the titledcompound (125 mg, 67%). MS (CI): mass calcd. for C₂₁H₂₉FN₄O₂, 388.23;m/z found, 389.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.48-8.39 (m, 1H),8.08 (d, J=1.4, 1H), 7.54 (m, 1H), 7.14 (d, J=8.2, 1H), 4.72 (s, 2H),4.45-4.37 (m, 1H), 4.09-3.99 (m, 2H), 3.86-3.73 (m, 1H), 3.29-3.21 (m,1H), 3.16-3.07 (m, 1H), 2.86-2.69 (m, 2H), 2.41-2.30 (m, 2H), 2.19-2.01(m, 4H), 1.90-1.81 (m, 1H), 1.05 (d, J=6.7, 6H).

Example 254

racemic3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propane-1,2-diol

The title compound is a side product found when water opens the epoxide,5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine,using the conditions in Example 253 Step B. MS (CI): mass calcd. forC₁₇H₂₀FN₃O₃, 333.15; m/z found, 334.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.28 (s, 1H), 7.99 (d, J=1.4, 1H), 7.50 (m, 1H), 7.20 (d, J=8.2, 1H),6.64 (s, 2H), 4.93 (d, J=5.1, 1H), 4.64 (t, J=5.6, 1H), 4.02-3.97 (m,1H), 3.92-3.83 (m, 2H), 3.82-3.77 (m, 1H), 3.46 (t, J=5.6, 2H),2.35-2.27 (m, 2H), 2.14-1.95 (m, 3H), 1.86-1.78 (m, 1H).

Example 255

racemic1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-morpholinopropan-2-ol

The title compound was prepared using analogous conditions described inExample 253 using morpholine in Step B. MS (CI): mass calcd. forC₂₁H₂₇FN₄O₃, 402.21; m/z found, 403.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.48-8.44 (m, 1H), 8.09 (d, J=1.5, 1H), 7.58-7.53 (m, 1H), 7.16 (d,J=8.2, 1H), 4.67 (s, 2H), 4.18 (s, 1H), 4.03 (d, J=4.9, 2H), 3.88-3.83(m, 1H), 3.79 (s, 4H), 2.76 (s, 2H), 2.68 (s, 2H), 2.60 (s, 2H),2.40-2.33 (m, 2H), 2.17 (dt, J=9.3, 5.4, 2H), 2.09-2.00 (m, 1H),1.93-1.84 (m, 1H)

Example 256

racemic4-(3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)thiomorpholine1,1-dioxide

The title compound was prepared using analogous conditions described inExample 253 using thiomorpholine 1,1-dioxide in Step B. MS (CI): masscalcd. for C₂₁H₂₇FN₄O₄S, 450.17; m/z found, 451.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.98 (m, 1H), 7.48 (m, 1H), 7.18 (d,J=8.2, 1H), 6.62 (s, 2H), 4.94 (d, J=4.4, 1H), 3.96-3.79 (m, 4H),3.12-3.03 (m, 4H), 3.02-2.95 (m, 4H), 2.68 (dd, J=13.2, 4.3, 1H),2.61-2.52 (m, 1H), 2.31-2.23 (m, 2H), 2.13-1.92 (m, 3H), 1.83-1.73 (m,1H).

Example 257

5-(4-Cyclobutyl-2-fluoro-3-(pyridazin-4-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 with DMSO as the solvent, heating for 2 hoursat 80° Celsius via microwave radiation and substituting Intermediate Band 4-bromo-pyridazine hydrobromide. MS (ESI): mass calcd. forC₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ9.12-9.05 (m, 1H), 9.01-8.95 (m, 1H), 8.47-8.41 (m, 1H), 8.11 (d, J=1.5Hz, 1H), 7.91-7.82 (m, 1H), 7.35-7.28 (m, 1H), 6.83-6.75 (m, 1H), 4.84(s, 2H), 3.63-3.49 (m, 1H), 2.28-2.06 (m, 4H), 2.08-1.90 (m, 1H),1.90-1.79 (m, 1H).

Example 258

3-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 with DMSO as the solvent, heating for 2 hoursat 140° Celsius via microwave radiation and substituting Intermediate Band 2-amino-3-chloropyrazine. MS (ESI): mass calcd. for C₁₈H₁₇FN₆O,352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.29-8.23(m, 3H), 8.01 (d, J=1.5 Hz, 3H), 7.76-7.68 (m, 3H), 7.61 (d, J=3.0 Hz,3H), 7.28 (d, J=8.3 Hz, 3H), 7.14 (d, J=3.0 Hz, 3H), 6.70 (s, 11H),3.62-3.49 (m, 3H), 2.17-2.00 (m, 12H), 1.98-1.83 (m, 3H), 1.81-1.67 (m,3H).

Example 259

5-(4-Cyclobutyl-2-fluoro-3-(pyrazin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 160 with DMSO as the solvent, heating for 2 hoursat 80° Celsius via microwave radiation and substituting Intermediate Band 2-fluoropyrazine. MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/zfound, 337.9 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=1.3 Hz, 1H),8.49-8.42 (m, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.12-8.03 (m, 2H), 7.85-7.76(m, 1H), 7.23 (s, 1H), 4.70 (s, 2H), 3.68-3.56 (m, 1H), 2.26-2.08 (m,4H), 2.03-1.89 (m, 1H), 1.87-1.76 (m, 1H).

Example 260

5-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-4-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 with pyridine as a solvent, heating at 80°Celsius for 18 hours and substituting 4-chloropyrimidine hydrochloride.MS (ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13 m/z found, 338.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 8.62 (d, J=5.8 Hz, 1H), 8.47-8.45(m, 1H), 8.09 (d, J=1.4 Hz, 1H), 7.82 (m, 1H), 7.24 (d, J=8.3 Hz, 1H),7.02 (dd, J=5.8, 1.0 Hz, 1H), 4.67 (s, 2H), 3.59 (m, 1H), 2.25-2.08 (m,4H), 2.03-1.89 (m, 1H), 1.86-1.76 (m, 1H).

Example 261

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N-isobutylpyrimidin-2-aminetrifluoroacetic acid salt

Step A:5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

Example 137 was prepared using conditions similar to those described inExample 101 with DMSO as a solvent, heating via microwave irradiation at120° Celsius for 1 hour and using 2,4-dichloropyrimidine.

Step B

The crude material from Step A was treated with 10 equivalents ofisobutylamine and heated via microwave irradiation at 140° Celsius for 1hour. The resulting mixture was subjected to FCC followed by reversephase HPLC to give 6 mg (6%) of the title compound. MS (ESI): masscalcd. for C₂₂H₂₅FN₆O, 408.21 m/z found, 409.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 10.38-10.29 (m, 1H), 8.38 (d, J=1.1 Hz, 1H), 8.22 (s, 1H), 7.99(d, J=6.8 Hz, 1H), 7.96-7.88 (m, 1H), 7.31-7.23 (m, 1H), 6.46 (d, J=6.8Hz, 1H), 3.63-3.49 (m, 1H), 2.94-2.84 (m, 2H), 2.31-1.96 (m, 4H),1.93-1.81 (m, 1H), 1.68-1.54 (m, 1H), 0.66 (d, J=6.7 Hz, 6H).

Example 262

Methyl-2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-benzoxazole-5-carboxylate

The title compound was prepared using analogous conditions described inExample 69 using methyl 2-(chloromethyl)benzo[d]oxazole-5-carboxylate.MS (ESI): mass calcd. for C₂₄H₂₁FN₄O₄, 448.15; m/z found, 449.1 [M+H]⁺.

Example 263

Methyl3-({[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetyl}amino)-4-hydroxybenzoate

Title compound was a side product from the preparation of Example 262.MS (ESI): mass calcd. for C₂₄H₂₃FN₄O₅, 466.17; m/z found, 467.1 [M+H]⁺.

Example 264

5-[4-Cyclobutyl-2-fluoro-3-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 69 using 4-bromomethyltetrahydropyran. MS (ESI): mass calcd. forC₂₀H₂₄FN₃O₂, 357.19; m/z found, 358.1 [M+H]⁺.

Example 265

4-[3-(5-Aminopyrazin-2-yl-6-cyclobutyl-2-fluorophenoxy]-3-(methylsulfonyl)benzonitrile

The title compound was prepared using analogous conditions described inExample 69 using 4-fluoro-3-(methylsulphonyl)benzonitrile. MS (ESI):mass calcd. for C₂₂H₁₉FN₄O₃, 438.12; m/z found, 439.1 [M+H]⁺.

Example 266

5-{3-[2,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 69 using 2,4-bis-(trifluoromethyl)fluorobenzene. MS (ESI): masscalcd. for C₂₂H₁₆F₇N₃O, 471.12; m/z found, 472.1 [M+H]⁺.

Example 267

5-{4-Cyclobutyl-3-[3-(dimethylamino)propoxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 243 utilizing 3-chloro-N,N-dimethylpropan-1-amine hydrochloride.MS (ESI): mass calcd. for C₁₉H₂₅FN₄O, 344.20; m/z found, 345.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 8.09 (d, J=1.3, 1H), 7.53 (m,1H), 7.14 (d, J=8.2, 1H), 4.73 (s, 2H), 4.06 (t, J=6.0, 2H), 3.88-3.71(m, 1H), 2.90-2.75 (m, 2H), 2.47 (s, 6H), 2.36-2.32 (m, 2H), 2.20-2.02(m, 5H), 1.89-1.84 (m, 1H).

Example 268

5-{4-Cyclobutyl-3-[2-(dimethylamino)ethoxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 243 utilizing 2-chloro-N,N-dimethylethanamine hydrochloride. MS(ESI): mass calcd. for C₁₈H₂₃FN₄O, 330.19; m/z found, 331.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.52-8.39 (m, 1H), 8.09 (d, J=1.5, 1H), 7.56 (m,1H), 7.16 (d, J=8.4, 1H), 4.64 (s, 2H), 4.25 (s, 2H), 3.84-3.79 (m, 1H),3.06 (s, 2H), 2.64 (s, 6H), 2.41-2.31 (m, 2H), 2.23-2.02 (m, 3H),1.93-1.83 (m, 1H).

Example 269

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,6-dimethylpyrimidin-2-amine

The title compound was prepared using analogous conditions described inExample 69 using 4-chloro-N,6-dimethylpyrimidin-2-amine. MS (ESI): masscalcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.2 [M+H]⁺.

Example 270

2-[6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenoxy]pyrimidin-4-amine

The title compound was prepared using analogous conditions described inExample 69 using 4-amino-2-chloropyrimidine and6-cyclobutyl-2-fluoro-3-{7-[(4-methylphenyl)-sulfonyl]-7H-pyrrolo[2,3-c]pyridazin-3-yl}phenol.MS (ESI): mass calcd. for C₂₀H₁₇FN₆O, 376.14; m/z found, 376.9 [M+H]⁺.

Example 271

5-{4-Cyclobutyl-3-[(6,7-difluoroquinoxalin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloro-6,7-difluoroquinoxaline. MS(ESI): mass calcd. for C₂₂H₁₆F₃N₅O, 423.13; m/z found, 424.0 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.86 (s, 1H), 8.31-8.21 (m, 1H), 8.06 (dd, J=1.5,0.7, 1H), 7.94 (dd, J=10.7, 8.3, 1H), 7.82-7.75 (m, 1H), 7.59 (dd,J=11.1, 8.1, 1H), 7.33 (d, J=8.3, 1H), 3.78-3.54 (m, 1H), 2.19 (t,J=8.9, 4H), 2.01-1.93 (m, 1H), 1.85-1.77 (m, 1H).

Example 272

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]quinazolin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloroquinazolin-4-amine. MS (ESI):mass calcd. for C₂₂H₁₉FN₆O, 402.16; m/z found, 403.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.29 (d, J=2.1, 1H), 8.10-7.97 (m, 2H), 7.69 (dd, J=13.1,6.9, 2H), 7.55 (d, J=8.5, 1H), 7.41-7.33 (m, 1H), 7.26 (d, J=8.3, 1H),3.71 (t, J=9.0, 1H), 2.28-2.08 (m, 4H), 2.02-1.92 (m, 1H), 1.81 (d,J=9.6, 1H).

Example 273

2-Amino-5-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carbonitrile

The title compound was prepared using analogous conditions described inExample 69 using 2-amino-5-bromopyrimidine-4-carbonitrile. MS (ESI):mass calcd. for C₁₉H₁₆FN₇O, 377.14; m/z found, 377.9 [M+H]⁺.

Example 274

Methyl2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-benzoxazole-5-carboxylate

The title compound was prepared using analogous conditions described inExample 69 using methyl 2-(chloromethyl)benzo[d]oxazole-5-carboxylate.MS (ESI): mass calcd. for C₂₄H₂₁FN₄O₄, 448.15; m/z found, 449.1 [M+H]⁺.

Example 275

Methyl3-({[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetyl}amino)-4-hydroxybenzoate

Title compound was a side product from the preparation of Example 274.MS (ESI): mass calcd. for C₂₄H₂₃FN₄O₅, 466.17; m/z found, 467.1 [M+H]⁺.

Example 276

[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetonitrile

The title compound was prepared using analogous conditions described inExample 69 using chloroacetonitrile. MS (ESI): mass calcd. forC₁₆H₁₅FN₄O, 298.12; m/z found, 299.1 [M+H]⁺.

Example 277

5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 69 using 3-chloropyridazine. MS (ESI): mass calcd. forC₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺.

Example 278

5-[4-Cyclopropyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-bromopyrimidine and3-(5-aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenol. MS (ESI): masscalcd. for C₁₇H₁₄FN₅O, 323.12; m/z found, 324.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.62 (d, J=4.8, 2H), 8.25 (dd, J=2.3, 1.5, 1H), 8.04 (d, J=1.5,1H), 7.69-7.61 (m, 1H), 7.29-7.21 (m, 1H), 6.95-6.86 (m, 1H), 2.07-1.87(m, 1H), 0.95-0.82 (m, 2H), 0.74-0.65 (m, 2H).

Example 279

2-[3-(5-Aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloropyrimidin-4-amine and3-(5-aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenol. MS (ESI): masscalcd. for C₁₇H₁₅FN₆O, 338.13; m/z found, 339.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.31-8.22 (m, 1H), 8.03 (d, J=1.5, 1H), 7.88 (d, J=5.9, 1H),7.65-7.57 (m, 1H), 6.85 (d, J=8.5, 1H), 6.25 (d, J=5.9, 1H), 2.02-1.91(m, 1H), 0.91 (m, 2H), 0.75-0.68 (m, 2H).

Example 280

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-2-yl)methoxy]phenyl}pyrazin-2-aminetrifluoroacetic acid salt

The title compound was prepared using analogous conditions described inExample 69 using 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride.MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.2 [M+H]⁺.

Example 281

Methyl2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-oxazole-4-carboxylateTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using methyl 2-(chloromethyl)oxazole-4-carboxylate. MS (ESI):mass calcd. for C₂₀H₁₉FN₄O₄, 398.14; m/z found, 399.1 [M+H]⁺.

Example 282

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-oxazole-4-carboxylicAcid Trifluoroacetic Acid Salt

Title compound was a side product obtained in the preparation of Example284. MS (ESI): mass calcd. for C₁₉H₁₇FN₄O₄, 384.12; m/z found, 385.1[M+H]⁺.

Example 283

5-[3-(1,3-Benzothiazol-2-ylmethoxy-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 2-(chloromethyl)benzo[d]thiazole. MS (ESI): mass calcd.for C₂₂H₁₉FN₄OS, 406.13; m/z found, 407.1 [M+H]⁺.

Example 284

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-4-yl)methoxy]phenyl}pyrazin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride.MS (ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺.

Example 285

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-5-yl)methoxy]phenyl}pyrazin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 5-(chloromethyl)-1-methyl-1H-imidazolehydrochloride. MS(ESI): mass calcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺.

Example 286

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-3-carbonitrile TrifluoroaceticAcid Salt

The title compound was prepared using analogous conditions described inExample 69 using 2-(chloromethyl)nicotinonitrile. MS (ESI): mass calcd.for C₁₉H₂₀FN₅O, 375.15; m/z found, 354.1 [M+H]⁺.

Example 287

5-{4-Cyclobutyl-2-fluoro-3-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}pyrazin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 4-(chloromethyl)-2-methylthiazole. MS (ESI): masscalcd. for C₁₉H₁₉FN₄OS, 370.13; m/z found, 371.0 [M+H]⁺.

Example 288

5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-ylmethoxy)phenyl]pyrazin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 3-(chloromethyl)pyridazine. MS (ESI): mass calcd. forC₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺.

Example 289

5-{3-[(5-Chloropyridin-2-yl)methoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 5-chloro-2-(chloromethyl)pyridine. MS (ESI): masscalcd. for C₂₀H₁₈FClN₄O, 384.12; m/z found, 385.0 [M+H]⁺.

Example 290

5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-2-carbonitrileTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 5-(chloromethyl)picolinonitrile. MS (ESI): mass calcd.for C₂₁H₁₈FN₅O, 375.15; m/z found, 376.1 [M+H]⁺.

Example 291

5-{4-Cyclobutyl-2-fluoro-3-[(5-methylisoxazol-3-yl)methoxy]phenyl}pyrazin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 3-(chloromethyl)-5-methylisoxazole. MS (ESI): masscalcd. for C₁₉H₁₉FN₄O₂, 354.15; m/z found, 355.1 [M+H]⁺.

Example 292

6-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-2-carbonitrileTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 69 using 6-(chloromethyl)picolinonitrile. MS (ESI): mass calcd.for C₂₁H₁₈FN₅O, 375.15; m/z found, 376.0 [M+H]⁺.

Example 293

2-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}-1H-isoindole-1,3(2H)-dione

The title compound was prepared using analogous conditions described inExample 69 using 2-(2-bromoethyl)isoindoline-1,3-dione. MS (ESI): masscalcd. for C₂₄H₂₁FN₄O₃, 432.16; m/z found, 433.0 [M+H]⁺.

Example 294

5-[3-(2-Aminoethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine

To a 200 mL round-bottomed flask containing2-{2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}-1H-isoindole-1,3(2H)-dione(550 mg, 1.27 mmol) were added a stir bar and EtOH (26 mL). The mixturewas then thoroughly sparged (bubbling N₂) before charging the flask withhydrazine monohydrate (1.00 mL, 21 mmol). The flask was then heated at77° Celsius for 22 hours. The reaction mixture was cooled to rt, dilutedwith EtOAc, washed with NaOH (1 N, ×3), dried over MgSO4, filtered andconcentrated to dryness to give the desired product (365 mg, 95%). MS(ESI): mass calcd. for C₁₆H₁₉FN₄O, 302.15; m/z found, 303.1 [M+H]⁺.

Example 295

5-{4-Cyclobutyl-2-fluoro-3-[2-(pyrazin-2-ylamino)ethoxy]phenyl}pyrazin-2-amineTrifluoroacetic Acid Salt

To a 5 mL microwave vial were added a spin-vane,5-[3-(2-aminoethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine (47 mg,0.16 mmol), 2-fluoropyrazine (35 mg, 0.35 mmol), and Cs₂CO₃ (115 mg,0.35 mmol). The flask was thoroughly purged with nitrogen, charged withDMSO (1.0 mL), and heated at 100° Celsius for 14.5 hours before coolingto room temperature, filtering off the solids and subjecting thefiltrate to HPLC purification to give the title compound (26 mg, 34%).MS (ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺.

Example 296

N-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-2-amineTrifluoroacetic Acid Salt

The title compound was prepared using analogous conditions described inExample 295 using 2-chloropyrimidine. MS (ESI): mass calcd. forC₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺.

Example 297

N-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-4-amine

The title compound was prepared using analogous conditions described inExample 295 using 4-chloropyrimidine. MS (ESI): mass calcd. forC₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺.

Example 298

5-[4-Cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl]pyrazin-2-amineHydrogen Chloride Salt

The title compound was prepared using analogous conditions described inStep A of Example 68 using tert-butyl4-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)piperidine-1-carboxylate.MS (ESI): mass calcd. for C₂₀H₂₅FN₄O, 356.20; m/z found, 357.1 [M+H]⁺.

Example 299

racemic5-[4-Cyclobutyl-2-fluoro-3-(piperidin-3-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inStep A of Example 68 utilizing racemic tert-butyl3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)piperidine-1-carboxylate.MS (ESI): mass calcd. for C₂₀H₂₅FN₄O, 356.20; m/z found, 357.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 7.53(m, 1H), 7.13 (d, J=8.2, 1H), 4.69 (s, 2H), 3.96-3.83 (m, 2H), 3.80-3.68(m, 1H), 3.65-3.57 (m, 1H), 3.52-3.35 (m, 1H), 2.93-2.76 (m, 2H),2.55-2.38 (m, 1H), 2.38-2.27 (m, 2H), 2.19-1.83 (m, 7H), 1.63-1.44 (m,1H).

Example 300

racemic5-[4-Cyclobutyl-2-fluoro-3-(pyrrolidin-3-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inStep A of Example 68 utilizing racemic tert-butyl3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluoro-phenoxy)methyl)pyrrolidine-1-carboxylate.MS (ESI): mass calcd. for C₁₉H₂₃FN₄O, 342.19; m/z found, 343.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃) δ 9.90 (s, 1H), 8.43 (d, J=1.7, 1H), 8.08 (d,J=1.1, 1H), 7.53 (m, 1H), 7.14 (d, J=8.2, 1H), 4.73 (s, 2H), 4.12-3.97(m, 2H), 3.78-3.64 (m, 2H), 3.55-3.39 (m, 2H), 3.38-3.28 (m, 1H),2.99-2.81 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.01 (m, 4H), 1.92-1.83 (m,1H).

Example 301

5-[3-(Azetidin-3-ylmethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inStep A of Example 68 utilizingtert-butyl-3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)azetidine-1-carboxylate.MS (ESI): mass calcd. for C₁₈H₂₁FN₄O, 328.17; m/z found, 329.5 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 8.27 (s, 1H), 7.98 (s, 1H),7.52 (m, 1H), 7.20 (d, J=8.2, 1H), 6.65 (s, 2H), 4.10 (d, J=5.7, 2H),4.06-3.96 (m, 2H), 3.87-3.77 (m, 2H), 3.77-3.69 (m, 1H), 3.17-3.09 (m,1H), 2.33-2.19 (m, 2H), 2.15-1.92 (m, 3H), 1.87-1.74 (m, 1H).

Example 302

racemic5-[4-Cyclobutyl-2-fluoro-3-(pyrrolidin-2-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inStep A of Example 68 utilizing racemic tert-butyl2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate.MS (ESI): mass calcd. for C₁₉H₂₃FN₄O, 342.19; m/z found, 343.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=1.5, 1H), 7.97 (d, J=1.4, 1H),7.49 (m, 1H), 7.19 (d, J=8.2, 1H), 6.63 (s, 2H), 3.98-3.88 (m, 2H),3.85-3.76 (m, 1H), 3.59-3.52 (m, 1H), 3.01-2.91 (m, 2H), 2.32-2.24 (m,2H), 2.17-1.89 (m, 5H), 1.84-1.70 (m, 3H), 1.61-1.51 (m, 1H).

Example 303

racemic 51-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-piperidin-1-ylpropan-2-ol

The title compound was prepared using analogous conditions described inExample 51 utilizing piperidine. MS (ESI): mass calcd. for C₂₂H₂₉FN₄O₂,400.23; m/z found, 401.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.28-8.23 (m,1H), 8.03 (d, J=1.5, 1H), 7.50 (m, 1H), 7.22 (d, J=8.2, 1H), 4.58 (s,2H), 4.43-4.34 (m, 1H), 4.04-3.94 (m, 2H), 3.95-3.85 (m, 1H), 3.34 (dd,J=8.4, 4.9, 2H), 3.23 (d, J=13.2, 2H), 2.37 (m, 2H), 2.25-2.12 (m, 2H),2.08 (m, 1H), 1.93-1.79 (m, 5H), 1.68 (s, 2H).

Example 304

racemic1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-(methylamino)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 utilizing methylamine. MS (ESI): mass calcd. for C₁₈H₂₃FN₄O₂,346.18; m/z found, 347.4 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.32-8.23 (m,1H), 8.11-8.00 (m, 1H), 7.51 (m, 1H), 7.23 (d, J=8.2, 1H), 4.29-4.21 (m,1H), 4.08-3.98 (m, 2H), 3.95-3.86 (m, 1H), 3.39-3.35 (m, 1H), 3.25-3.20(m, 1H), 2.79 (s, 3H), 2.44-2.34 (m, 2H), 2.23-2.06 (m, 3H), 1.96-1.86(m, 1H).

Example 305

racemic1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-[(1-methylethyl)amino]propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 utilizing isopropylamine. MS (ESI): mass calcd. forC₂₀H₂₇FN₄O₂, 374.21; m/z found, 375.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.31-8.21 (m, 1H), 7.97 (d, J=1.4, 1H), 7.50 (m, 1H), 7.19 (d, J=8.2,1H), 6.64 (s, 2H), 5.73 (s, 1H), 4.19-4.07 (m, 1H), 3.99-3.89 (m, 2H),3.88-3.76 (m, 1H), 3.27-3.22 (m, 1H), 3.15-3.07 (m, 1H), 2.98-2.88 (m,1H), 2.34-2.23 (m, 2H), 2.14-1.90 (m, 3H), 1.86-1.73 (m, 1H), 1.24-1.14(m, 6H).

Example 306

racemic1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-pyrrolidin-1-ylpropan-2-ol

The title compound was prepared using analogous conditions described inExample 51 utilizing pyrrolidine. MS (ESI): mass calcd. for C₂₁H₂₇FN₄O₂,386.21; m/z found, 387.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.54-8.36 (m,1H), 8.09 (d, J=1.4, 1H), 7.55 (m, 1H), 7.15 (d, J=8.2, 1H), 4.71 (s,2H), 4.23-4.12 (m, 1H), 4.02 (d, J=5.1, 2H), 3.94-3.78 (m, 1H), 3.20 (s,1H), 2.99-2.92 (m, 1H), 2.91-2.83 (m, 2H), 2.78-2.68 (m, 3H), 2.42-2.31(m, 2H), 2.21-2.01 (m, 3H), 1.93-1.81 (m, 5H).

Example 307

racemic1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-(dimethylamino)propan-2-ol

The title compound was prepared using analogous conditions described inExample 51 utilizing dimethylamine. MS (ESI): mass calcd. forC₁₉H₂₅FN₄O₂, 360.20; m/z found, 361.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.26 (s, 1H), 7.97 (d, J=1.4, 1H), 7.49 (m, 1H), 7.19 (d, J=8.2, 1H),6.64 (s, 2H), 5.41 (s, 1H), 4.08 (s, 1H), 3.91-3.79 (m, 3H), 2.88-2.82(m, 1H), 2.81-2.72 (m, 1H), 2.51 (s, 6H), 2.32-2.23 (m, 2H), 2.12-1.92(m, 3H), 1.84-1.73 (m, 1H).

Example 308

diastereomeric mixture of1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}pyrrolidin-3-ol

The title compound was prepared using analogous conditions described inExample 51 utilizing racemic 3-hydroxypyrrolidine. MS (ESI): mass calcd.for C₂₁H₂₇FN₄O₃, 402.21; m/z found, 403.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.28-8.23 (m, 1H), 7.97 (d, J=1.4, 1H), 7.48 (m, 1H), 7.19(d, J=8.4, 1H), 6.63 (s, 2H), 5.46-5.14 (m, 1H), 4.96 (d, J=14.5, 1H),4.28-4.21 (m, 1H), 4.06-3.98 (m, 1H), 3.93-3.79 (m, 3H), 3.07-2.64 (m,6H), 2.33-2.24 (m, 2H), 2.13-1.94 (m, 4H), 1.86-1.75 (m, 1H), 1.70-1.57(m, 1H).

Example 309

racemic1-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-piperazin-1-ylpropan-2-ol

The title compound was prepared using analogous conditions described inExample 51 utilizing piperazine. MS (ESI): mass calcd. for C₂₁H₂₈FN₅O₂,401.22; m/z found, 402.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s,1H), 8.00 (d, J=1.4, 1H), 7.50 (m, 1H), 7.21 (d, J=8.3, 1H), 6.66 (s,2H), 4.95 (s, 1H), 4.01-3.82 (m, 4H), 2.97 (t, J=4.9, 4H), 2.63 (s, 3H),2.58-2.53 (m, 1H), 2.52-2.49 (m, 2H), 2.47-2.41 (m, 1H), 2.35-2.26 (m,2H), 2.16-1.94 (m, 3H), 1.88-1.78 (m, 1H).

Example 310

racemic1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}pyrimidin-2(1H)-one

The title compound was prepared using analogous conditions described inExample 51 utilizing 2-pyrimidinone. MS (ESI): mass calcd. forC₂₁H₂₂FN₅O₃, 411.17; m/z found, 412.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.55 (dd, J=4.2, 2.8, 1H), 8.32-8.26 (m, 1H), 8.10 (dd, J=6.5, 2.8,1H), 8.00 (d, J=1.5, 1H), 7.52 (m, 1H), 7.22 (d, J=8.3, 1H), 6.64 (s,2H), 6.43 (dd, J=6.4, 4.2, 1H), 5.48 (d, J=5.8, 1H), 4.33 (dd, J=13.0,3.3, 1H), 4.19 (t, J=7.1, 1H), 3.96 (d, J=5.2, 2H), 3.85 (dd, J=17.7,8.7, 1H), 3.71 (dd, J=13.0, 9.0, 1H), 2.32 (m, 2H), 2.10 (m, 2H), 2.00(dd, J=17.9, 7.9, 1H), 1.87-1.78 (m, 1H).

Example 311

racemic1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}-1,3-dihydro-2H-benzimidazol-2-one

The title compound was prepared using analogous conditions described inExample 51 utilizing 1H-benzo[d]imidazol-2(3H)-one. MS (ESI): masscalcd. for C₂₄H₂₄FN₅O₃, 449.19; m/z found, 450.0 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.29-8.24 (m, 1H), 7.99 (d, J=1.5, 1H),7.50 (m, 1H), 7.23-7.13 (m, 2H), 7.06-6.93 (m, 3H), 6.63 (s, 2H), 5.36(d, J=4.9, 1H), 4.18 (s, 1H), 4.00-3.91 (m, 3H), 3.89-3.78 (m, 2H),2.32-2.20 (m, 2H), 2.14-2.01 (m, 2H), 1.99-1.89 (m, 1H), 1.79 (dd,J=18.7, 9.1, 1H).

Example 312

racemic1-{3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}imidazolidin-2-one

The title compound was prepared using analogous conditions described inExample 51 utilizing imidazolidin-2-one. MS (ESI): mass calcd. forC₂₀H₂₄FN₅O₃, 401.19; m/z found, 402.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆)δ 8.28 (s, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 7.21 (d, J=8.2, 1H), 6.64(s, 2H), 6.31 (s, 1H), 5.20 (d, J=4.7, 1H), 3.94 (s, 1H), 3.87 (s, 3H),3.25 (dd, J=19.6, 11.7, 5H), 3.09 (dd, J=13.8, 7.0, 1H), 2.30 (d, J=7.9,2H), 2.15-2.05 (m, 2H), 2.00 (d, J=9.9, 1H), 1.82 (d, J=9.1, 1H).

Example 313

2′-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5,5′-bipyrimidin-2-amine

Step A:5-(3-((5-Bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

To a microwave vial containing a stir-bar was added3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (100 mg, 0.386mmol), 5-bromo-2-chloropyrimidine (74 mg, 0.39 mmol), cesium carbonate(188 mg, 0.580), and DMSO (2 mL). The vial was sealed and heated in themicrowave for 30 minutes at 120° Celsius. The mixture was cooled to rtthen passed through a syringe filter and the filtrate subjected to HPLCpurification to give the title compound. ¹H NMR (500 MHz, 2 mL) δ 8.69(d, J=1.5, 2H), 8.24 (s, 1H), 8.10 (s, 1H), 7.79-7.69 (m, 1H), 7.27 (d,J=8.3, 1H), 3.72-3.58 (m, 1H), 2.23-2.10 (m, 3H), 2.02-1.94 (m, 1H),1.89-1.75 (m, 1H).

Step B:2′-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5,5′-bipyrimidin-2-amine

5-(3-((5-Bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine(60 mg, 0.14 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (32 mg,0.14 mmol) were added to a sealable microwave vial equipped with astir-bar. 1,4-Dioxane (0.58 mL) and Na₂CO₃ (2 M, 0.14 mL) were added Andthe mixture sparged with Ar for 10 min before adding Pd(dppf)Cl₂.CH₂Cl₂(5 mg, 0.007 mmol) and heating the reaction mixture at 80° Celsius for15 hours. The reaction was then cooled to rt, diluted with water (5 mL),and extracted with ethyl acetate (3×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered, and concentrated to dryness.The crude product was purified by HPLC to give the title compound. MS(ESI): mass calcd. for C₂₂H₁₉FN₈O, 430.17; m/z found, 431.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.83 (s, 2H), 8.67 (s, 2H), 8.23 (s, 1H), 8.16(s, 1H), 7.82-7.74 (m, 1H), 7.30 (d, J=8.3, 1H), 3.68 (p, J=8.9, 1H),2.31-2.08 (m, 4H), 2.07-1.92 (m, 1H), 1.92-1.76 (m, 1H).

Intermediate J

3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenol

Step A: tert-Butyl(2-fluoro-6-methylphenoxy)dimethylsilane

To a stirred solution of 2-fluoro-6-methylphenol (176 mg, 1.40 mmol) inDCM (6.3 mL), cooled to 0° Celsius, were added imidazole (142 mg, 2.09mmol) followed by tert-butyldimethylsilyl chloride (231 mg, 1.54 mmol).The flask was warmed to rt and stirred for 2 hours The reaction mixturewas then poured in to water (50 mL) and extracted with DCM (3×50 mL).The combined organic extracts were dried over sodium sulfate, filtered,and concentrated to dryness to provide the title compound that was usedwithout further purification. ¹H NMR (500 MHz, CDCl₃) δ 6.91-6.85 (m,2H), 6.80-6.73 (m, 1H), 2.24 (t, J=0.7, 3H), 1.02 (s, 9H), 0.20 (d,J=2.5, 6H).

Step B:(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic acid

To a 25 mL flask vial were added a stir-bar, 2.1 mL dry THF, and2,2,6,6-tetramethylpiperidine (0.22 mL, 1.0 mmol). The flask was cooledto −78° Celsius and then treated with n-BuLi (0.48 mL, 1.9 mmol, 2.5 Min hexanes) over 2 minutes. The resultant mixture was stirred for 5 minand then warmed to 0° Celsius. After 30 min, the mixture was re-cooledto −78° Celsius and treated with B(O-iPr)₃ (0.26 mL, 1.1 mmol) over 4min. After 15 min, a solution consisting oftert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane (247 mg, 1.03 mmol)in dry THF (2.1 mL) was added over the course of 6 min and stirringcontinued for 1 hour at −78° Celsius. The mixture was then warmed to rt,treated with HOAc (0.5 mL), and then poured into water (100 mL) andstirred for 5 min. The aqueous mixture was then extracted with EtOAc(3×100 mL), the combined extracts dried over Na₂SO₄, filtered, andconcentrated to dryness to give the title compound, which was useddirectly in the next synthetic step.

Step C:5-(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine

(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic acid(292 mg, 1.03 mmol), 2-amino-5-bromopyrazine (179 mg, 1.03 mmol),1,4-dioxane (6.1 mL), and Na₂CO₃ (2.1 mL, 2 M) were added to a microwavevial and the resultant mixture sparged with argon for 10 minutes.Pd(dppf)Cl₂.DCM was then added the mixture, the vial sealed, and thenheated at 80° Celsius for 16 hours. The reaction mixture was then cooledto rt, diluted with water (5 mL), and extracted with EtOAc (4×5 mL). Thecombined organic extracts were then dried over Na₂SO₄, filtered, andconcentrated to dryness to provide the title compound. This compound wasused directly in the next synthetic step without purification.

Step D: 3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenol

5-(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine(342 mg, 1.03 mmol) was dissolved in THF (1.2 mL) at rt and then treatedwith tetrabutylammonium fluoride (1.2 mL, 1 M in THF). The reaction wasstirred for 1 hour at rt, before diluting with water (10 mL) andextracting with EtOAc (10 mL×4). The combined organic extracts werewashed with brine, dried over Na₂SO₄, filtered, and concentrated todryness. The crude product was purified by FCC to provide the titlecompound. ¹H NMR (500 MHz, CD₃OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.01 (d,J=1.5, 1H), 7.09 (m, 1H), 6.94 (m, 1H), 2.25 (s, 3H).

Intermediate K

3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol

Step A: 2-Fluoro-6-vinylphenol

To a round-bottomed flask containing a stir-bar were added,methyltriphenylphosphonium bromide (5.6 g, 16 mmol) and anhydrous THF(50 mL). The mixture was stirred until homogeneous and then cooled to 0°Celsius. The flask was then charged drop-wise with n-BuLi (6.85 mL, 2.5M in hexanes). The resultant solution was stirred for 30 minutes andthen transferred via cannula to a stirred mixture of3-fluoro-2-hydroxybenzaldehyde (1 g, 7 mmol) and THF (28 mL) at rt underan argon atmosphere. The resultant mixture was stirred for 3 h beforequenching with saturated NH₄Cl (50 mL), diluting with water, andextracting with ether (3×100 mL). The combined ethereal extracts weredried over magnesium sulfate, filtered through a plug of silica gel, andthen concentrated to dryness to provide the title compound that was usedwithout further purification. ¹H NMR (500 MHz, CDCl₃) δ 7.20 (m, 1H),7.04-6.92 (m, 2H), 6.80 (m, 1H), 5.81 (dd, J=17.8, 1.3, 1H), 5.69 (s,1H), 5.35 (dd, J=11.2, 1.3, 1H).

Step B: tert-Butyl(2-fluoro-6-vinylphenoxy)dimethylsilane

The title compound was prepared in an analogous way totert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane in Step A ofIntermediate J using 2-fluoro-6-vinylphenol. ¹H NMR (500 MHz, CDCl₃) δ7.26 (m, 1H), 7.03 (dd, J=17.8, 11.1, 1H), 6.96 (m, 1H), 6.89-6.81 (m,1H), 5.68 (dd, J=17.8, 1.3, 1H), 5.34-5.24 (m, 1H), 1.02 (s, 9H), 0.19(d, J=2.4, 6H).

Step C: tert-Butyl(2-ethyl-6-fluorophenoxy)dimethylsilane

To a stirred solution oftert-butyl(2-fluoro-6-vinylphenoxy)dimethylsilane (1.18 g, 4.67 mmol) inethyl acetate (61 mL) under nitrogen, was added 497 mg of 10% palladiumon carbon. The flask was then equipped with a hydrogen containingballoon and the reaction mixture stirred rapidly for 4 hours. Thehydrogen balloon was removed, the reaction mixture sparged withnitrogen, and then filtered through a plug of Celite®, eluting withEtOAc. The filtrate was concentrated to dryness to afford the titlecompound that was used without further purification. ¹H NMR (500 MHz,CDCl₃) δ 6.94-6.85 (m, 2H), 6.85-6.77 (m, 1H), 2.65 (q, J=7.6, 2H), 1.19(t, J=7.5, 3H), 1.02 (s, 9H), 0.21 (d, J=2.7, 6H).

Step D: 3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol

The title compound was prepared in an analogous way to3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol in Steps B-D ofIntermediate J using tert-butyl(2-ethyl-6-fluorophenoxy)dimethylsilane.¹H NMR (500 MHz, CD₃OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.02 (d, J=1.5,1H), 7.12 (dd, J=8.0, 7.3, 1H), 6.99-6.93 (m, 1H), 2.68 (q, J=7.5, 2H),1.21 (t, J=7.5, 3H).

Intermediate L

3-(5-Aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenol

The title compound was prepared using conditions similar to thosedescribed in Method 2 for3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol usingcycloproplyzinc bromide in Step B. ¹H NMR (500 MHz, CD₃OD) δ 8.29-8.24(m, 1H), 8.02 (d, J=1.5, 1H), 7.16-7.05 (m, 1H), 6.65 (dd, J=8.2, 1.3,1H), 2.28-2.11 (m, 1H), 1.02-0.90 (m, 2H), 0.72-0.63 (m, 2H).

Intermediate M

3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isopropylphenol

The title compound was prepared using conditions similar to thosedescribed in Method 2 for3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol using isoproplyzincbromide in Step B. MS (ESI): mass calcd. for C₁₃H₁₄FN₃O, 247.11; m/zfound, 248.1 [M+H]⁺.

Intermediate N

3-(5-Aminopyrazin-2-yl)-2-fluoro-6-propylphenol

The title compound was prepared using conditions similar to thosedescribed in Method 2 for3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol using proplyzincbromide in Step B. MS (ESI): mass calcd. for C₁₃H₁₄FN₃O, 247.11; m/zfound, 248.1 [M+H]⁺.

Example 314

5-[2-Fluoro-4-methyl-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloropyrimidine and3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol. MS (ESI): mass calcd.for C₁₅H₁₂FN₅O, 297.10; m/z found, 298.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD)δ 8.61 (d, J=4.8, 2H), 8.22-8.20 (m, 1H), 8.20-8.19 (m, 1H), 7.73-7.68(m, 1H), 7.27-7.24 (m, 1H), 7.22 (m, 1H), 2.23 (d, J=0.7, 3H).

Example 315

2-[3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloropyrimidin-4-amine and3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol. MS (ESI): mass calcd.for C₁₅H₁₃FN₆O, 312.11; m/z found, 313.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD)δ 8.29-8.25 (m, 1H), 8.04 (d, J=1.5, 1H), 7.87 (d, J=5.9, 1H), 7.63-7.53(m, 1H), 7.15 (d, J=8.1, 1H), 6.25 (d, J=5.9, 1H), 2.22 (s, 3H).

Example 316

5-[4-Ethyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloropyrimidine and3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluorophenol. MS (ESI): mass calcd.for C₁₆H₁₄FN₅O, 311.12; m/z found, 312.3 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.61(d, J=4.8, 2H), 8.20 (dd, J=6.7, 1.6, 2H), 7.74 (dd, J=8.3, 7.5, 1H),7.29-7.21 (m, 2H), 2.63 (q, J=7.6, 2H), 1.17 (t, J=7.6, 3H)

Example 317

2-[3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloropyrimidine-4-amine and3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluorophenol. MS (ESI): mass calcd.for C₁₆H₁₅FN₆O, 326.13; m/z found, 327.3 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.27(m, 1H), 8.04 (d, J=1.5, 1H), 7.87 (d, J=5.9, 1H), 7.63 (m, 1H), 7.17(dd, J=8.1, 1.3, 1H), 6.24 (d, J=5.9, 1H), 2.62 (q, J=7.6, 2H), 1.19 (t,J=7.6, 3H)

Example 318

5-[2-Fluoro-4-(1-methylethyl)-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloropyrimidine and3-(5-aminopyrazin-2-yl)-2-fluoro-6-isopropylphenol. MS (ESI): masscalcd. for C₁₇H₁₆FN₅O, 325.13; m/z found, 326.3 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.62 (d, J=4.8, 2H), 8.25 (s, 1H), 8.04 (d, J=1.5, 1H), 7.72(t, J=7.9, 1H), 7.28 (dd, J=8.4, 1.4, 1H), 7.25 (m, 1H), 3.18-3.10 (m,1H), 1.22 (d, J=6.9, 6H).

Example 319

5-[2-Fluoro-4-propyl-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 101 heating at 120° Celsius via microwaveirradiation for 1 hour and using 2-chloropyrimidine and3-(5-aminopyrazin-2-yl)-2-fluoro-6-propylphenol. MS (ESI): mass calcd.for C₁₇H₁₆FN₅O, 325.13; m/z found, 326.3 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD)δ 8.61 (d, J=4.8, 2H), 8.25 (s, 1H), 8.04 (d, J=1.5, 1H), 7.71-7.62 (m,1H), 7.27-7.23 (m, 1H), 7.20 (dd, J=8.2, 1.4, 1H), 2.58 (t, J=7.6, 2H),1.66-1.51 (m, 2H), 0.90 (t, J=7.3, 3H).

Example 320

5-(4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

Step A: tert-Butyl(2-cyclohexyl-6-fluorophenoxy)dimethylsilane

A solution consisting of(2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (0.832 g, 2.73 mmol)and bis(tri-tert-butylphosphine)palladium(0) (0.070 g, 0.14 mmol) anddry THF (5 mL) was treated with cyclohexylzinc(II) bromide (7.0 mL, 3.5mmol, 0.5 M in THF). The resultant mixture was heated for 45 minutes at50° C., cooled to rt, and concentrated to dryness. The resultant residuewas subjected to FCC purification to the title compound (0.841 g, 89%)which was used without purification.

Step B:(3-((tert-Butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)boronicacid

A solution consisting of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0mmol) and dry THF (2 mL) was cooled to −78° C. and treated withn-butyllithium (1.1 mL, 2.75 mmol, 2.5 M in hexanes). After stirring for5 minutes, the reaction was warmed to rt for 5 minutes before coolingback down to −78° C. The reaction was then treated withtert-butyl(2-cyclohexyl-6-fluorophenoxy)dimethylsilane (0.719 g, 2.33mmol) and triisopropyl borate (0.60 mL, 2.6 mmol) and stirred for 5minutes. The reaction mixture was warmed to rt, quenched with saturatedNH₄Cl (2 mL), and extracted with EtOAc (2×5 mL). The combined organicextracts were washed with brine (3×5 mL), dried over MgSO₄, filtered,and concentrated to dryness to yield the title compound (0.833 g, 101%),which was used without purification.

Step C:5-(3-((tert-Butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)pyrazin-2-amine

A mixture of(3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)boronicacid (0.821 g, 2.33 mmol), 5-bromopyrazin-2-amine (0.40 g, 2.3 mmol),K₂CO₃ (0.659 g, 4.77 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (0.086 g, 0.12 mmol),deoxygenated toluene (10 mL), and deoxygenated deionized water (10 mL)was heated for 16 hours at 80° Celsius. The reaction mixture was thencooled to rt, diluted with dichloromethane (25 mL), and washed withbrine (2×25 mL). The organic layer was dried over MgSO₄, filtered, andconcentrated to dryness to yield the title compound (0.936 g, 100%)which was used without purification.

Step D: 3-(5-Aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol

A solution consisting of5-(3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)pyrazin-2-amine(936 mg, 2.33 mmol) and THF (15 mL) was treated with tetrabutylammoniumfluoride (5 mL, 5 mmol, 1 M in THF). The reaction mixture was stirredfor 16 hours at which point it was concentrated to dryness and purifiedby FCC to yield the title compound (0.403 g, 60%) which was used withoutfurther purification. MS (ESI): mass calcd. for C₁₆H₁₈FN₃O, 287.14; m/zfound, 288.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.47-8.45 (m, 1H), 8.09(d, J=1.5, 1H), 7.32 (m, 1H), 7.06-7.03 (m, 1H), 5.60 (d, J=6.3, 1H),4.65 (s, 2H), 3.00-2.92 (m, 1H), 1.94-1.81 (m, 4H), 1.80-1.74 (m, 1H),1.52-1.38 (m, 4H), 1.33-1.25 (m, 1H).

Step E:5-(4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

A mixture consisting of3-(5-aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol (0.05 g, 0.2 mmol),2-chloropyrimidine (0.025 g, 0.22 mmol), K₂CO₃ (0.05 g, 0.4 mmol), and18-crown-6 (0.01 g, 0.04 mmol), and DMSO (2 mL) was heated via microwaveirradiation for 1 hour at 120° Celsius. After cooling to roomtemperature, the reaction mixture was filtered and purified directly viaHPLC to yield the title compound (42 mg, 65%). MS (ESI): mass calcd. forC₂₀H₂₀FN₅O, 365.17; m/z found, 366.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.63-8.60 (m, 2H), 8.28-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.80-7.76 (m,1H), 7.31-7.23 (m, 2H), 2.81-2.74 (m, 1H), 1.83-1.68 (m, 5H), 1.53-1.43(m, 2H), 1.35-1.24 (m, 3H).

Example 321

5-(4-(Cyclohexylmethyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using (cyclohexylmethyl)zinc(II) bromide in Step A. MS(ESI): mass calcd. for C₂₁H₂₂FN₅O, 379.18; m/z found, 380.1 [M+H]⁺. ¹HNMR (500 MHz, CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.26 (d, J=1.5, 1H),8.21-8.19 (m, 1H), 7.75-7.71 (m, 1H), 7.27-7.24 (m, 1H), 7.20-7.15 (m,1H), 2.49 (d, J=7.1, 2H), 1.68-1.60 (m, 5H), 1.55-1.47 (m, 1H),1.17-1.09 (m, 3H), 0.98-0.88 (m, 2H).

Example 322

5-(2-Fluoro-4-isopentyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using isopentylzinc(II) bromide in Step A. MS (ESI): masscalcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.65-8.59 (m, 2H), 8.28-8.26 (m, 1H), 8.21-8.19 (m, 1H),7.77-7.73 (m, 1H), 7.29-7.20 (m, 2H), 2.65-2.57 (m, 2H), 1.56-1.48 (m,1H), 1.46-1.39 (m, 2H), 0.85 (s, 3H), 0.83 (s, 3H).

Example 323

5-(2-Fluoro-4-isobutyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using isobutylzinc(II) bromide in Step A. MS (ESI): masscalcd. for C₁₈H₁₈FN₅O, 339.15; m/z found, 340.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.27 (d, J=1.4, 1H), 8.20 (m, 1H), 7.75(t, J=7.8, 1H), 7.25 (m, 1H), 7.22-7.19 (m, 1H), 2.49 (d, J=7.3, 2H),1.91-1.84 (m, 1H), 0.88 (d, J=6.6, 6H).

Example 324

5-(2-Fluoro-4-neopentyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using neopentylzinc(II) bromide in Step A. MS (ESI): masscalcd. for C₁₉H₂₀FN₅O, 353.17; m/z found, 354.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.61 (d, J=4.8, 2H), 8.26-8.25 (m, 1H), 8.21 (s, 1H), 7.74 (t,J=7.9, 1H), 7.24 (m, 1H), 7.22-7.19 (m, 1H), 2.53 (s, 2H), 0.94 (s, 9H).

Example 325

2-(3-(5-Aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using 2-chloropyrimidin-4-amine in Step E. MS (ESI): masscalcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.26-8.25 (m, 1H), 8.13 (d, J=1.5, 1H), 8.06 (d, J=7.0, 1H),7.80 (m, 1H), 7.32-7.29 (m, 1H), 6.51 (d, J=7.0, 1H), 2.79-2.71 (m, 1H),1.89-1.80 (m, 4H), 1.78-1.73 (m, 1H), 1.56-1.47 (m, 2H), 1.44-1.26 (m,3H).

Example 326

2-(3-(5-Aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using (cyclohexylmethyl)zinc(II) bromide in Step A and2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. forC₂₁H₂₃FN₆O, 394.19; m/z found, 395.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.28-8.26 (m, 1H), 8.11 (d, J=1.5, 1H), 8.05 (d, J=7.0, 1H), 7.76 (t,J=7.9, 1H), 7.22-7.19 (m, 1H), 6.51 (d, J=7.1, 1H), 2.53 (d, J=7.2, 2H),1.73-1.65 (m, 5H), 1.60-1.52 (m, 1H), 1.23-1.14 (m, 3H), 1.04-0.94 (m,2H).

Example 327

2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isopentylphenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using isopentylzinc(II) bromide in Step A and2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. forC₁₉H₂₁FN₆O, 368.18; m/z found, 369.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.27-8.26 (m, 1H), 8.11 (d, J=1.5, 1H), 8.05 (d, J=7.0, 1H), 7.77 (t,J=7.9, 1H), 7.26-7.23 (m, 1H), 6.51 (d, J=7.0, 1H), 2.68-2.62 (m, 2H),1.62-1.54 (m, 1H), 1.52-1.46 (m, 2H), 0.91 (d, J=6.5, 6H).

Example 328

2-(3-(5-Aminopyrazin-2-yl)-2-fluoro-6-isobutylphenoxy)pyrimidin-4-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using isobutylzinc(II) bromide in Step A and2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. forC₁₈H₁₉FN₆O, 354.16; m/z found, 355.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.28-8.26 (m, 1H), 8.12 (d, J=1.5, 1H), 8.05 (d, J=7.0, 1H), 7.77 (t,J=7.9, 1H), 7.24-7.21 (m, 1H), 6.50 (d, J=7.0, 1H), 2.53 (d, J=7.3, 2H),1.97-1.87 (m, 1H), 0.94 (d, J=6.6, 6H).

Example 329

5-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2-carboxamide

The title compound was prepared using analogous conditions to thosedescribed in Example 69 utilizing 5-bromo-2-cyanopyrimidine. MS (ESI):mass calcd. for C₁₉H₁₇FN₆O, 380.14; m/z found, 381.1 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.56 (s, 2H), 8.27 (s, 1H), 8.10 (d, J=1.5, 1H), 7.88-7.81(m, 1H), 7.40 (d, J=8.2, 1H), 3.76-3.64 (m, 1H), 2.33-2.14 (m, 5H),2.10-1.97 (m, 1H), 1.93-1.80 (m, 1H).

Example 330

5-(4-Cyclobutyl-2-fluoro-3-(thiazolo[4,5-b]pyridin-2-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 69 utilizing 2-chlorothiazolo[4,5-b]pyridine. MS(ESI): mass calcd. for C₂₀H₁₆FN₅O, 393.11; m/z found, 394.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.52 (dd, J=4.8, 1.7, 1H), 8.45 (dd, J=8.0,1.7, 1H), 8.33-8.28 (m, 1H), 8.03 (d, J=1.5, 1H), 7.91-7.83 (m, 1H),7.42-7.34 (m, 2H), 6.72 (br s, 2H), 3.67 (p, J=8.9, 1H), 2.27-2.09 (m,4H), 2.03-1.89 (m, 1H), 1.84-1.73 (m, 1H).

Example 331

5-(4-Cyclobutyl-2-fluoro-3-((5-methylthieno[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrazin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 69 utilizing4-chloro-5-methylthieno[2,3-d]pyrimidine. MS (ESI): mass calcd. forC₂₁H₁₈FN₅OS, 407.12; m/z found, 408.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.56 (s, 1H), 8.29-8.25 (m, 1H), 8.01 (d, J=1.5, 1H), 7.82-7.76 (m,1H), 7.61 (d, J=1.4, 1H), 7.32 (d, J=8.3, 1H), 6.70 (s, 2H), 3.63-3.53(m, 1H), 2.66 (d, J=1.3, 3H), 2.31-2.22 (m, 1H), 2.22-2.12 (m, 1H),2.10-2.01 (m, 1H), 2.01-1.95 (m, 1H), 1.94-1.84 (m, 1H), 1.78-1.69 (m,1H).

Example 332

N⁴-(2-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethyl)pyrimidine-2,4-diamine

The title compound was prepared using analogous conditions described inExample 295 utilizing 2-amino-4-chloropyrimidine. MS (ESI): mass calcd.for C₂₀H₂₂FN₇O, 395.19; m/z found, 396.2 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD)δ 8.30-8.24 (m, 1H), 8.03 (d, J=1.5, 1H), 7.64 (br s, 1H), 7.50-7.43 (m,1H), 7.19 (d, J=8.2, 1H), 5.93 (d, J=6.1, 1H), 4.14 (t, J=5.4, 2H), 3.83(m, 1H), 3.78-3.67 (m, 2H), 2.31-2.21 (m, 2H), 2.17-2.06 (m, 2H),2.05-1.93 (m, 1H), 1.87-1.78 (m, 1H).

Example 333

3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenol

The title compound was prepared in a manner analogous to that describedfor Intermediate K. MS (ESI): mass calcd. for C₁₂H₁₂FN₃O, 233.10; m/zfound, 234.1 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.26 (dd, J=2.3, 1.5 Hz, 1H), 8.02(d, J=1.5 Hz, 1H), 7.12 (dd, J=8.0, 7.3 Hz, 1H), 6.99-6.93 (m, 1H), 2.68(q, J=7.5 Hz, 2H), 1.21 (t, J=7.5 Hz, 3H)

Example 334

5-[4-Cyclopentyl-2-fluoro-3-pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using cyclopentylzinc(II) bromide in Step A and5-bromopyrimidin-2-amine in Step C. MS (ESI): mass calcd. forC₁₉H₁₈FN₅O, 351.15; m/z found, 352.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.61 (d, J=4.8 Hz, 2H), 8.55 (d, J=1.2 Hz, 2H), 7.41-7.35 (m, 1H),7.34-7.28 (m, 1H), 7.25 (t, J=4.8 Hz, 1H), 3.25-3.15 (m, 1H), 2.00-1.88(m, 2H), 1.87-1.73 (m, 2H), 1.71-1.53 (m, 4H).

Example 335

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclopentyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using cyclopentylzinc(II) bromide in Step A,5-bromopyrimidin-2-amine in Step C and 2-chloropyrimidin-4-amine in StepE. MS (ESI): mass calcd. for C₁₉H₁₉FN₆O, 366.16; m/z found, 367.2[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.45 (d, J=1.2 Hz, 2H), 7.87 (d, J=5.9Hz, 1H), 7.31-7.27 (m, 1H), 7.26-7.21 (m, 1H), 6.25 (d, J=5.9 Hz, 1H),3.26-3.10 (m, 1H), 2.04-1.91 (m, 2H), 1.85-1.74 (m, 2H), 1.70-1.55 (m,4H).

Example 336

2-[3-(5-Aminopyrazin-2-yl)-6-cyclopentyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using cyclopentylzinc(II) bromide in Step A and2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calcd. forC₁₉H₁₉FN₆O, 366.16; m/z found, 367.2 [M+H]⁺. ¹H NMR (500 MHz, MeOD) δ8.35-8.21 (m, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.87 (d, J=5.9 Hz, 1H),7.71-7.57 (m, 1H), 7.30-7.17 (m, 1H), 6.24 (d, J=5.9 Hz, 1H), 3.23-3.12(m, 1H), 2.03-1.89 (m, 2H), 1.88-1.74 (m, 2H), 1.72-1.52 (m, 4H).

Example 337

5-[4-Cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared in a manner analogous to that describedin Example 320 using cyclopentylzinc(II) bromide in Step A. MS (ESI):mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.2 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.61 (d, J=4.8 Hz, 2H), 8.24-8.21 (m, 1H), 8.11 (d, J=1.5Hz, 1H), 7.75-7.70 (m, 1H), 7.29 (dd, J=8.5, 1.4 Hz, 1H), 7.26-7.22 (m,1H), 3.25-3.10 (m, 1H), 2.01-1.88 (m, 2H), 1.87-1.70 (m, 2H), 1.70-1.56(m, 4H).

Example 338

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-3-amine

The title compound was prepared in a manner analogous to that describedin Example 160 using 6-fluoropyridazin-3-amine. MS (ESI): mass calcd.for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹H NMR (500 MHz, MeOD)δ 8.26 (dd, J=2.3, 1.4 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.72-7.61 (m,1H), 7.25 (d, J=8.3 Hz, 1H), 7.22 (d, J=9.4 Hz, 1H), 7.08 (d, J=9.4 Hz,1H), 3.66 (p, J=9.0 Hz, 1H), 2.27-2.09 (m, 4H), 2.05-1.93 (m, 1H),1.87-1.77 (m, 1H).

Example 339

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-ylmethoxy)phenyl]pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 243 using 2-(chloromethyl)pyrimidine. MS (ESI): mass calcd. forC₁₉H₁₈FN₅O, 351.15; m/z found, 352.2 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.84 (d, J=5.0 Hz, 2H), 8.27 (dd, J=2.4, 1.5 Hz, 1H), 8.03 (d, J=1.5 Hz,1H), 7.52 (dd, J=8.2, 7.4 Hz, 1H), 7.48 (t, J=5.0 Hz, 1H), 7.24-7.17 (m,1H), 5.24 (s, 2H), 4.00-3.85 (m, 1H), 2.33-2.21 (m, 2H), 2.21-2.08 (m,2H), 2.08-1.94 (m, 1H), 1.92-1.77 (m, 1H).

Example 340

5-{3-[(4-Bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using analogous conditions described inExample 243 using 1-bromo-4-(bromomethyl)benzene. MS (ESI): mass calcd.for C₂₁H₁₉BrFN₃O, 427.07; m/z found, 428.1 [M+H]⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.29 (dd, J=2.3, 1.5 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.57-7.52(m, 2H), 7.52-7.46 (m, 1H), 7.43-7.35 (m, 2H), 7.23-7.13 (m, 1H), 5.02(s, 2H), 3.76 (p, J=8.8 Hz, 1H), 2.32-2.20 (m, 2H), 2.20-2.07 (m, 2H),2.07-1.96 (m, 1H), 1.91-1.77 (m, 1H).

Example 341

5-(4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)pyrimidin-2-amine

To a sealable vial were added5-{3-[(4-bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine(42 mg, 0.098 mmol) and (2-aminopyrimidin-5-yl)boronic acid (13 mg,0.098 mmol), followed by 1,4-dioxane (0.5 mL) and Na₂CO₃ (0.2 mL, 2 M).The mixture was sparged with argon for 10 minutes thenPd(dppf)Cl₂.CH₂Cl₂ (4 mg, 0.005 mmol) was added and the vial was sealed.The vial was heated at 80° C. for 3 hours before cooling it to RT andpartitioning its contents between EtOAc (50 mL) and water (50 mL). Theaqueous layer was washed with EtOAc (50 mL) and the combined organicextracts were dried with Na₂SO₄, filtered and concentrated to dryness.The resultant residue was purified by prep-HPLC to provide the titlecompound. MS (ESI): mass calcd. for C₂₅H₂₃FN₆O, 442.19; m/z found, 443.1[M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 2H), 8.30-8.27 (m, 1H), 8.10(d, J=1.5 Hz, 1H), 7.67-7.62 (m, 2H), 7.62-7.57 (m, 2H), 7.56-7.49 (m,1H), 7.20 (d, J=8.3 Hz, 1H), 5.11 (s, 2H), 3.81 (t, J=8.9 Hz, 1H),2.34-2.22 (m, 2H), 2.21-2.08 (m, 2H), 2.01 (q, J=10.0 Hz, 1H), 1.92-1.80(m, 1H).

Example 342

5-(4-Cyclobutyl-2-fluoro-3-{[4′-trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pyrazin-2-amine

The title compound was prepared in an analogous manner to Example 341using (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₂₈H₂₃F₄N₃O, 493.18; m/z found, 494.1 [M+H]⁺. ¹H NMR (400 MHz, MeOD) δ8.32-8.28 (m, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.88-7.81 (m, 2H), 7.78-7.70(m, 4H), 7.62-7.57 (m, 2H), 7.51 (dd, J=8.2, 7.4 Hz, 1H), 7.20 (d, J=8.3Hz, 1H), 5.12 (s, 2H), 3.93-3.74 (m, 1H), 2.35-2.22 (m, 2H), 2.22-2.09(m, 2H), 2.08-1.94 (m, 1H), 1.90-1.79 (m, 1H).

Example 343

5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

Step A: 1-bromo-3-fluoro-2-(methoxymethoxy)benzene

To a solution consisting of 2-bromo-6-fluorophenol (5.0 g, 26 mmol),DIPEA (9.0 mL, 52.4 mmol) and CH₂Cl₂ (131 mL) was addedchloro(methoxy)methane (2.2 mL, 29 mmol). The reaction mixture wasstirred at RT for 1 h, then washed with sat. aq. NaHCO₃ (30 mL). Theorganic layer was isolated, concentrated to dryness and the resultantresidue was purified by FCC to afford the title compound (5.5 g, 89%).¹H NMR (500 MHz, CDCl₃) δ 7.36-7.31 (m, 1H), 7.10-7.03 (m, 1H),6.97-6.92 (m, 1H), 5.20 (s, 2H), 3.65 (s, 3H).

Step B: 1-Cyclohexyl-3-fluoro-2-(methoxymethoxy)benzene

To a round-bottomed flask, were added a stir bar,1-bromo-3-fluoro-2-(methoxymethoxy)benzene (12.9 g, 12.3 mmol) and THF(41 mL). The flask was sealed with a rubber septa and flushed with N₂for 5 minutes. Bis(tri-tert-butylphosphine)palladium(0) (473 mg, 0.92mmol) was then added to the flask, followed by cyclohexylzinc(II)bromide (0.5 M in THF, 37 mL, 19 mmol). The reaction mixture was heatedat 60° C. for 1 h, cooled to RT, concentrated onto silica gel andpurified by FCC to afford the title compound (2.4 g, 80%). ¹H NMR (400MHz, CDCl₃) δ 7.02-6.96 (m, 2H), 6.96-6.86 (m, 1H), 5.11 (s, 2H), 3.61(s, 3H), 3.07-2.97 (m, 1H), 1.89-1.77 (m, 4H), 1.46-1.21 (m, 6H).

Step C: (4-Cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)boronic Acid

To a solution of 2,2,6,6-tetramethylpiperidine (3.2 mL, 19 mmol) and THF(40 mL), at −78° C., was added n-butyllithium (2.3 M in hexanes, 8.2 mL,19 mmol) drop-wise. The reaction mixture was allowed to warm to 0° C.,stirred 5 min, and cooled to −78° C. Triisopropyl borate (4.3 mL, 19mmol) was added, followed by a solution consisting of1-cyclohexyl-3-fluoro-2-(methoxymethoxy)benzene (3.0 g, 13 mmol) and THF(20 mL). The mixture was stirred for 5 min at −78° C., warmed to RT, andquenched with sat. NH₄Cl (20 mL). The mixture was partitioned betweenwater (20 mL) and EtOAc (40 mL). The organic phases were separated andthe aqueous solution was further extracted with EtOAc (2×40 mL). Theorganic extracts were combined, concentrated to dryness and the crudeproduct was used directly.

Step D:5-(4-Cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)pyrimidin-2-amine

A solution consisting of(4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)boronic acid (1.4 g, 5.0mmol), 2-amino-5-bromopyrimidine (0.95 g, 5.5 mmol) and THF (25 mL) wassparged with N₂ for 10 min. A solution of Na₂CO₃ (25 mL, 50 mmol, 2 M)was then added and the mixture was further sparged with N₂ for 20 min.1,1″bis(di-t-butylphosphino)ferrocene palladium dichloride (162 mg, 0.25mmol) was added, the reaction mixture was heated at 50° C. for 2 h,cooled to RT and diluted with EtOAc (50 mL). The organic phase wasisolated, concentrated onto silica, and purified by FCC to provide thetitle compound (0.84 g, 51%). MS (ESI): mass calcd. for C₁₈H₂₂FN₃O₂,331.17; m/z found, 332.3 [M+H]⁺.

Step E: 3-(2-Aminopyrimidin-5-yl)-6-cyclohexyl-2-fluorophenol

To a solution consisting of5-(4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)pyrimidin-2-amine (840mg, 2.5 mmol) and CH₂Cl₂ (25 mL), was added TFA (0.6 mL, 7.6 mmol), andthe reaction mixture was stirred at RT for 12 h. The reaction mixturewas then diluted with CH₂Cl₂ (95 mL) and washed with sat. aq. NaHCO₃ (50mL). The organic layer was isolated, concentrated to dryness, and theresulting residue was purified by FCC to afford the title compound.

Step F:5-[4-Cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

To a microwave vial equipped with a stir-bar, were added3-(2-aminopyrimidin-5-yl)-6-cyclohexyl-2-fluorophenol (100 mg, 0.35mmol), 2-chloropyrimidine (42 mg, 0.35 mmol), K₂CO₃ (96 mg, 0.70 mmol),18-crown-6 (5 mg, 0.02 mmol) and DMA (0.5 mL). The vial was capped andirradiated in a microwave reactor for 10 min at 110° C., before coolingto RT and diluting with EtOAc (10 mL) and water (5 mL). The organiclayer was isolated, concentrated to dryness and the resultant residuewas purified by prep-HPLC to provide the title compound (65 mg, 39%). MS(ESI): mass calcd. for C₂₀H₂₀FN₅O 365.17; m/z found, 366.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.62 (d, J=4.8 Hz, 2H), 8.56 (d, J=1.2 Hz, 2H),7.44-7.36 (m, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 7.26 (t, J=4.8 Hz, 1H),2.85-2.70 (m, 1H), 1.86-1.64 (m, 5H), 1.59-1.39 (m, 2H), 1.35-1.21 (m,3H).

Example 344

5-{3-[(4-Aminopyrimidin-2-yl)oxy]-4-cyclohexyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared using analogous conditions to thosedescribed in Example 343 using 4-amino-2-chloropyrimidine in step F. MS(ESI): mass calcd. for C₂₀H₂₁FN₆O, 380.18; m/z found, 381.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.44 (d, J=1.4 Hz, 2H), 7.87 (d, J=6.0 Hz, 1H),7.34-7.26 (m, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.25 (d, J=6.0 Hz, 1H),2.84-2.68 (m, 1H), 1.87-1.65 (m, 5H), 1.52-1.20 (m, 5H).

Example 345

3-(5-Aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol

The title compound was prepared in a manner analogous to that describedin Steps A-D for Example 320 using cyclohexylzinc(II) bromide in Step A.MS (ESI): mass calcd. for C₁₆H₁₈FN₃O, 287.14; m/z found, 288.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.47-8.45 (m, 1H), 8.09 (d, J=1.5 Hz, 1H),7.36-7.29 (m, 1H), 7.06-7.03 (m, 1H), 5.60 (d, J=6.3 Hz, 1H), 4.65 (s,2H), 3.00-2.92 (m, 1H), 1.94-1.81 (m, 4H), 1.80-1.74 (m, 1H), 1.52-1.38(m, 4H), 1.33-1.25 (m, 1H).

Example 346

3-(5-Aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenol

The title compound was prepared in a manner analogous to that describedin Steps A-D for Example 320 using (cyclohexylmethyl)zinc(II) bromide inStep A. ¹H NMR (500 MHz, CDCl₃) δ 8.47-8.45 (m, 1H), 8.09 (d, J=1.5 Hz,1H), 7.30-7.26 (m, 1H), 6.95-6.93 (m, 1H), 5.62 (s, 1H), 4.66 (s, 2H),2.56 (d, J=7.1 Hz, 2H), 1.74-1.58 (m, 7H), 1.23-1.13 (m, 3H), 1.05-0.94(m, 2H).

Example 347

5-{3-[(2-Aminopyridin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 using 2-amino-4-bromopyridine with DMSO as thesolvent, heating via microwave irradiation at 140° C. for 10 hours. MS(ESI): mass calcd. for C₁₉H₁₈FN₅O, 351.15; m/z found, 352.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.49-8.46 (m, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.93(d, J=5.9 Hz, 1H), 7.83-7.76 (m, 1H), 7.24 (d, J=8.3 Hz, 1H), 6.30-6.24(m, 1H), 5.89 (d, J=2.2 Hz, 1H), 4.71 (s, 2H), 4.40 (s, 2H), 3.64-3.53(m, 1H), 2.29-2.07 (m, 4H), 2.03-1.90 (m, 1H), 1.87-1.76 (m, 1H).

Example 348

5-{3-[(6-Aminopyrazin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 using 2-amino-6-chloropyrazine with DMSO as thesolvent, heating via microwave irradiation at 140° C. for 6 hours. MS(ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.28-8.24 (m, 1H), 8.00 (d, J=1.5 Hz, 1H),7.72-7.65 (m, 1H), 7.55 (d, J=3.8 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 6.70(s, 2H), 6.51 (s, 2H), 3.60-3.47 (m, 1H), 2.22-2.03 (m, 4H), 1.99-1.85(m, 1H), 1.83-1.70 (m, 1H).

Example 349

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-5-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 using 5-bromopyrimidine with DMSO as thesolvent, heating via microwave irradiation at 140° C. for 2 hours. MS(ESI): mass calcd. for C₁₈H₁₆FN₅O, 337.13; m/z found, 338.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.46-8.42 (m, 1H), 8.40 (s, 2H),8.09 (d, J=1.5 Hz, 1H), 7.87-7.80 (m, 1H), 7.31-7.27 (m, 1H), 4.78 (s,2H), 3.69-3.58 (m, 1H), 2.30-2.10 (m, 4H), 2.07-1.92 (m, 1H), 1.90-1.76(m, 1H).

Example 350

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-4-amine

The title compound was prepared using conditions similar to thosedescribed in Example 164 using 6-chloro-4-pyridazinamine with DMSO asthe solvent, heating via microwave irradiation at 180° C. for 2 hours.MS (ESI): mass calcd. for C₁₈H₁₇FN₆O, 352.14; m/z found, 353.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (d, J=2.0 Hz, 1H), 8.25 (s, 1H),8.04-7.97 (m, 1H), 7.74-7.67 (m, 1H), 7.26 (d, J=8.3 Hz, 1H), 6.68 (s,2H), 6.60 (s, 2H), 6.23 (d, J=2.0 Hz, 1H), 3.58-3.46 (m, 1H), 2.17-2.02(m, 4H), 1.98-1.84 (m, 1H), 1.80-1.69 (m, 1H).

Example 351

5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine

Step A:(3-bromo-6-(tert-butyl)-2-fluorophenoxy)(tert-butyl)dimethylsilane

To a 100 mL round-bottomed flask were added a stir-bar, THF (38.0 mL),tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (5.0 g, 18mmol), and N,N,N′,N′-tetramethylethylenediamine (1.6 mL, 19 mmol). Theflask was cooled to −78° C. and then treated with sec-BuLi (14 mL, 20mmol, 1.4 M in hexanes) over 6 min. The resulting mixture was stirredfor 2 hr, before treating it with a solution consisting of carbontetrabromide (8.7 mL, 26 mmol) and THF (8.0 mL) over the course of 2min. The resulting mixture was stirred for an additional 2 h at −78° C.The reaction mixture was then warmed to RT and stirred another 18 h. Thereaction mixture was then poured into sat. aq NH₄Cl and extracted withEtOAc (200 mL). The organic phase was isolated, dried over Na₂SO₄,filtered and concentrated to dryness. Purification by FCC yielded thetitle compound.

Step B: 3-Bromo-6-(tert-butyl)-2-fluorophenol

To a 100 mL round-bottomed flask were added a stir-bar,(3-bromo-6-(tert-butyl)-2-fluorophenoxy)(tert-butyl)dimethylsilane (6.4g, 18 mmol), THF (44.0 mL) and TBAF (25.0 g, 24.0 mmol, 1M in THF). Themixture was stirred for 2 hr and then poured into NH₄Cl (100 mL, sat.aq.). The aqueous mixture was then extracted with EtOAc (200 mL), theorganic extract was dried over Na₂SO₄, filtered and concentrated todryness. Purification by FCC yielded the title compound.

Step C: 2-(3-Bromo-6-(tert-butyl)-2-fluorophenoxy)pyrimidine

To a 20 mL microwave vial were added a stir-bar,3-bromo-6-(tert-butyl)-2-fluorophenol (1.4 g, 5.7 mmol),2-chloropyrimidine (0.76 g, 6.3 mmol), cesium carbonate (3.6 g, 11mmol), and acetonitrile (11.0 mL). The mixture was heated at 80° C. for18 hr. The reaction mixture was filtered and the filtrate was directlysubjected to FCC to provide the title compound (0.95 g, 51%)¹H NMR (400MHz, CDCl₃) δ 8.58 (d, J=4.8 Hz, 2H), 7.37 (dd, J=8.8, 6.7 Hz, 1H), 7.12(dd, J=8.8, 1.9 Hz, 1H), 7.09-7.05 (m, 1H), 1.35 (s, 9H).

Step D:5-4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl-1H-pyrrolo[2,3-b]pyridine

5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridinewas coupled to 2-(3-bromo-6-(tert-butyl)-2-fluorophenoxy)pyrimidine inan analogous manner to Step D in Intermediate A to give the titlecompound (10 mg, 8%). MS (ESI): mass calcd. for C₂₁H₁₉FN₄O, 362.15; m/zfound, 363.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.11 (s, 1H), 8.60 (d,J=4.8 Hz, 2H), 8.53-8.46 (m, 1H), 8.15-8.08 (m, 1H), 7.40-7.30 (m, 3H),7.11-7.01 (m, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 1.45-1.41 (m, 9H).

The following Examples 1-36 summarized in Table 4 are prophetic andunless otherwise specified, can be readily synthesized by a personskilled in the art utilizing the above described reaction schemes or bysynthesis routes generally known to a person skilled in the art. Oneskilled in the art based on presently disclosed compounds would concludethe following prophetic compounds to be active against FLAP.

TABLE 4 Prophetic Examples STRUCTURE No. NAME

1 5-(2-fluoro-4-(pentan-3-yl)-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

2 5-(fluoro-4-methyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

3 5-(4-ethyl-2-fluoro-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

4 5-(2-fluoro-4-propyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

5 5-(2-fluoro-4-isopropyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

6 5-(4-cyclopropyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrimidn-2-amine

7 5-(2-fluoro-4-isobutyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

8 5-(2-fluoro-4-neopentyl-3-(pyrimidin-2- yloxy)phenyl)pyrimidin-2-amine

9 5-(2-fluoro-4-(pentan-3-yl)-3-(pyrimidin-2-yloxy)phenyl)pyrimidin-2-amine

10 5-(4-cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrimidin-2-amine

11 5-(4-(cyclohexylmethyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrimidin-2- amine

12 5-(2-fluoro-4-isopentyl-3-(pyrimidin-2-yloxy)phenyl)pyrimidin-2-amine

13 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-4-methylpyrimidin-2- amine

14 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-4-methylpyrimidin-2- amine

15 3-chloro-5-(4-cyclobutyl-2- fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridin-2-amine

16 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-chloropyridin-2-amine

17 2-amino-5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)nicotinonitrile

18 2-amino-5-(4-(tert-butyl)-2- fluoro-3-(pyrimidin-2-yloxy)phenyl)nicotinonitrile

19 5-(4-cyclobutyl-2-fluoro-3- (pyrimidin-2-yloxy)phenyl)-3-fluoropyridin-2-amine

20 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-fluoropyridin-2-amine

21 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-(trifluoromethyl)pyridin- 2-amine

22 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-(trifluoromethyl)pyridin- 2-amine

23 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridine-2,3-diamine

24 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridine-2,3-diamine

25 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-methylpyrazin-2-amine

26 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-methylpyrazin-2-amine

27 3-chloro-5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2- amine

28 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-chloropyrazin-2-amine

29 3-amino-6-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazine-2- carbonitrile

30 3-amino-6-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazine-2- carbonitrile

31 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-fluoropyrazin-2-amine

32 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-fluoropyrazin-2-amine

33 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-methoxypyrazin-2- amine

34 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3-methoxypyrazin-2- amine

35 5-(4-cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazine-2,3-diamine

36 5-(4-(tert-butyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazine-2,3-diamineD) General Administration, Formulation, and Dosages

The present invention provides substituted heteroaryl ketone compoundswhich are useful as FLAP modulators.

The invention features a method for treating a subject in need thereofwith an FLAP-mediated disease and/or disorder, said method comprisingadministering to the subject a therapeutically effective amount of acompound of the invention. In particular, the invention also provides amethod for treating or inhibiting the progression of an FLAP-mediateddisease and/or disorder, or associated symptoms or complications thereofin a subject afflicted with such a disease and/or disorder, wherein themethod comprises administering to the subject a therapeuticallyeffective amount of a compound of the invention.

Embodiments of the present invention include a method wherein thecompound of Formula (I) is a FLAP modulator.

Embodiments of the present invention include a use of the compound ofFormula (I) in the manufacture of a medicament for treating anFLAP-mediated disease and/or disorder.

Embodiments of the present invention include a use of the compound ofFormula (I) as a medicine.

The compounds of Formula (I) have an FLAP-modulating effect and areuseful as therapeutic agents for various FLAP-mediated disorders and/ordisorders, or associated symptoms or complications, for example,respiratory disorders, cardiac and cardiovascular diseases, autoimmunedisorders, carcinogenesis, and associated symptoms or complicationsthereof.

The compounds of Formula (I) may be administered orally or parenterally,and after formulation into preparations suitable for the intendedadministration route, they can be used as therapeutic agents fortreating an FLAP-mediated disease and/or disorder. FLAP-mediateddiseases and/or disorders include, but are not limited, diseases and/ordisorders that are related to leukotriene synthesis pathway, andtherefore may be treated, controlled or in some cases prevented, bytreatment with the compounds of this invention.

One aspect of the present invention provides a method for the treatmentof diseases and/or disorders, or associated symptoms or complicationsthereof, responsive to the modulation of FLAP in a subject in needthereof which comprises administering to the subject a therapeuticallyor prophylactically effective amount of a compound of Formula (I) or aform thereof.

Another aspect of the present invention provides a method for thetreatment of a disease and/or disorder selected from the groupconsisting of respiratory diseases and/or disorders, cardiac andcardiovascular diseases and/or disorders, autoimmune diseases and/ordisorders, carcinogenesis, and associated symptoms or complicationsthereof, in a subject in need thereof which comprises administering tothe subject a therapeutically or prophylactically effective amount of acompound of Formula (I) or a form thereof.

More specifically, this invention is directed to a method of treatingexacerbations, non-allergic asthma, aspirin exacerbated respiratorydisease, pulmonary arterial hypertension, fibrotic lung diseases, acuterespiratory distress syndrome, obstructive sleep apnea and chronicobstructive pulmonary disease, or associated symptoms or complicationsthereof, in a subject afflicted with such a disease and/or disorder,wherein the method comprises administering to the subject atherapeutically or prophylactically effective amount of a compound ofFormula (I) or a form thereof.

Furthermore, this invention is directed to a method of treatingmyocardial infarction, atherosclerosis and coronary artery disease,stroke, aortic aneurisms, atherosclerosis, or associated symptoms orcomplications thereof, in a subject afflicted with such a disease and/ordisorder, wherein the method comprises administering to the subject atherapeutically or prophylactically effective amount of a compound ofFormula (I) or a form thereof.

Yet, this invention is also directed to a method of treating rheumatoidarthritis, inflammatory bowel disease, nephritis, spondyloarthritis,polymyositis, dermatomyositis, gouty effusions, systemic lupuserythematosus, systemic sclerosis, Alzheimer's disease, multiplesclerosis, allergic rhinitis, chronic sinusitis, allergic dermatitis andasthma, wherein the method comprises administering to the subject atherapeutically or prophylactically effective amount of a compound ofFormula (I) or a form thereof.

Finally, this invention is also directed to a method of treating tumorcell proliferation, differentiation, and apoptosis, tumor-associatedangiogenesis, as well as the migration and invasion of carcinoma cells,wherein the method comprises administering to the subject atherapeutically or prophylactically effective amount of a compound ofFormula (I) or a form thereof.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising at least one compound of Formula (I) or a formthereof, and a pharmaceutically acceptable carrier.

The invention also features a method for treating a subject in needthereof with an FLAP-mediated disease and/or disorder, said methodcomprising administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising at least one compoundof the invention.

Yet another aspect of the present invention relates to the use of acompound of Formula (I) or a form thereof, for the manufacture of amedicament useful for the treatment of an FLAP-mediated disease and/ordisorder in a subject in need thereof.

In a clinical use of the compounds of the invention,pharmaceutically-acceptable additives may be added thereto to formulatevarious preparations in accordance with the intended administrationroute thereof, and the preparations may be administered.

Various additives generally used in the field of pharmaceuticalcompositions may be used herein, including, for example, gelatin,lactose, sucrose, titanium oxide, starch, crystalline cellulose, methylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, cornstarch, microcrystalline wax, white petrolatum, magnesium metasilicatealuminate, anhydrous calcium phosphate, citric acid, trisodium citrate,hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester,polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castoroil, polyvinylpyrrolidone, magnesium stearate, palmitoleic acid, lightsilicic acid anhydride, talc, vegetable oil, benzyl alcohol, gum arabic,propylene glycol, polyalkylene glycol, cyclodextrin, andhydroxypropylcyclodextrin.

Combined with such additives, the compound of the invention may beformulated into various forms of preparations, for example, solidpreparations such as tablets, capsules, granules, powders andsuppositories; and liquid preparations such as syrups, elixirs andinjections. These preparations can be produced in any method known inthe field of pharmaceutical compositions. The liquid preparations may bein such a form that is dissolved or suspended in water or in any othersuitable medium before use. Especially for injections, the preparationmay be dissolved or suspended, if desired, in a physiological saline orglucose solution, and a buffer and a preservative may be added thereto.

The compounds of the invention are effective for animals, includinghumans and other mammals. Any ordinary physician, veterinarian orclinician may readily determine the necessity, if any, of treatment withan instant compound.

Those of skill in the treatment of diseases and/or disorders, orassociated symptoms or complications thereof, mediated by FLAP candetermine the effective daily amount from the test results presentedhereinafter and other information. The exact dosage and frequency ofadministration depends on the particular compound of invention used, theparticular disease and/or disorder, or associated symptoms orcomplications thereof, being treated, the severity of the disease and/ordisorder, or associated symptoms or complications thereof, beingtreated, the age, weight and general physical condition of theparticular patient as well as other medication the patient may betaking, as is well known to those skilled in the art. Furthermore, it isevident that said effective daily amount may be lowered or increaseddepending on the response of the treated patient and/or depending on theevaluation of the physician prescribing the compounds of the instantinvention. The effective daily amount ranges mentioned herein aretherefore only guidelines in practicing the present invention.

Preferably, the method for the treatment of the FLAP diseases and/ordisorders described in the present invention using any of the compoundsas defined herein, the dosage form will contain a pharmaceuticallyacceptable carrier containing between from about 1 mg to about 1000 mg;particularly from about 0.5 mg to about 500 mg of the compound, and maybe constituted into any form suitable for the mode of administrationselected. The dosages, however, may be varied depending upon therequirement of the subjects, the severity of the disease and/ordisorder, or associated symptoms or complications thereof, being treatedand the compound being employed. The use of either daily administrationor post-periodic dosing may be employed.

When the compound of the invention is, for example, put into clinicaluse, then its dose and its administration frequency may vary dependingon the sex, the age, the body weight and the condition of the patientand on the type and the range of the necessary treatment with thecompound. For oral administration, in general, the dose of the compoundmay be in a range of from about 0.01 mg/kg/day to about 100 mg/kg ofbody weight/day or in a range of from about 0.03 mg/kg/day to about 1mg/kg/day. The oral administration frequency is preferably from one to afew times per day. For parenteral administration, the dose may be in arange of from about 0.001 mg/kg/day to about 10 mg/kg/day, in a range offrom about 0.001 mg/kg/day to about 0.1 mg/kg/day or, in a range of fromabout 0.01 mg/kg/day to about 0.1 mg/kg/day. The parenteraladministration frequency is preferably from one to a few times per day.For oral administration, the compositions are preferably provided in theform of tablets containing from about 1.0 mg to about 1000 mg of theactive ingredient, particularly 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg,600 mg, 750 mg, 800 mg, 900 mg, and 1000 mg of the active ingredient forthe symptomatic adjustment of the dosage to the patient to be treated.The compounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

Ordinary physicians, veterinarians and clinicians may readily determinethe effective dose of the pharmaceutical compound necessary to treat,prevent, inhibit, retard or stop the intended disease, and may readilytreat the diseased patient with the compound.

The pharmaceutical compositions herein will contain, per unit dosageunit, e.g., tablet, capsule, powder, injection, suppository, teaspoonfuland the like, of from about 0.001 mg/kg/day to about 10 mg/kg/day(particularly from about 0.01 mg/kg/day to about 1 mg/kg/day; and, moreparticularly, from about 0.1 mg/kg/day to about 0.5 mg/kg/day) and maybe given at a dosage of from about 0.001 mg/kg/day to about 30 mg/kg/day(particularly from about 0.01 mg/kg/day to about 2 mg/kg/day, moreparticularly from about 0.1 mg/kg/day to about 1 mg/kg/day and even moreparticularly from about 0.5 mg/kg/day to about 1 mg/kg/day).

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, dry powders for reconstitution or inhalation,granules, lozenges, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, autoinjector devices orsuppositories for administration by oral, intranasal, sublingual,intraocular, transdermal, parenteral, rectal, vaginal, dry powderinhaler or other inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for 1 to 4 times perday, preferably once or twice per day administration; for example, aninsoluble salt of the active compound, such as the decanoate salt, maybe adapted to provide a depot preparation for intramuscular injection.

The preparation may contain the compound of the invention in an amountin a range of from about 1.0 to about 100% by weight or, in a range offrom about 1.0 to about 60% by weight of the preparation. Thepreparation may contain any other therapeutically-effective compound.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject.

Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

Some of the crystalline forms for the compounds may exist as polymorphsand as such are intended to be included in the present invention. Inaddition, some of the compounds may form solvates with water (i.e.,hydrates) or common organic solvents, and such solvates are intended tobe encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form or asindividual enantiomers or diasteromers by either stereospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers or diastereomers by standardtechniques, such as the formation of stereoisomeric pairs by saltformation with an optically active base, followed by fractionalcrystallization and regeneration of the free acid. The compounds mayalso be resolved by formation of stereoisomeric esters or amides,followed by chromatographic separation and removal of the chiralauxiliary. Alternatively, the compounds may be resolved using a chiralHPLC column. It is to be understood that all stereoisomers, racemicmixtures, diastereomers, cis-trans isomers, and enantiomers thereof areencompassed within the scope of the present invention.

E) Use

Dosages

For preparing pharmaceutical compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and gildants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e.TYLOSE™ available from Hoechst Celanese], polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrol idone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin, and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable gildants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W.R. Grace/Davison, and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active form of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate, cellulose acetate trimellitate), polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate and ethylacrylatecopolymers, methacrylate and methyl methacrylate copolymers and thelike. Sustained release tablets may also be made by film coating or wetgranulation using slightly soluble or insoluble substances in solution(which for a wet granulation acts as the binding agents) or low meltingsolids a molten form (which in a wet granulation may incorporate theactive ingredient). These materials include natural and syntheticpolymers waxes, hydrogenated oils, fatty acids and alcohols (i.e.beeswax, camauba wax, cetyl alcohol, cetylstearyl alcohol, and thelike), esters of fatty acids metallic soaps, and other acceptablematerials that can be used to granulate, coat, entrap or otherwise limitthe solubility of an active ingredient to achieve a prolonged orsustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions, and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth, and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose, and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene), and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agents include pharmaceutical gradelecithins. Suitable flocculating agents include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chloride,and the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms; however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.1 mg to about 5000 mg;preferably, the dose will be in the range of from about 1 mg to about100 mg per day for an average human. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the subject to be treated. Advantageously, acompound of the present invention may be administered in a single dailydose or the total daily dosage may be administered in divided doses oftwo, three or four times daily.

It is also apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedby those skilled in the art, and will vary with the particular compoundused, the mode of administration, the strength of the preparation, andthe advancement of the disease condition. In addition, factorsassociated with the particular subject being treated, including subjectage, weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level. The above dosagesare thus exemplary of the average case. There can, of course, beindividual instances where higher or lower dosage ranges are merited,and such are within the scope of this invention.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as FLAP modulators is required for a subject in needthereof.

In their use, the compounds of the invention may be combined with anyother therapeutic agents that are useful for the treatment of anFLAP-mediated disorder.

The combination includes not only the composition of compounds of theinvention and one other active substance but also the composition ofcompounds of the invention and two or more other active substances ornon-drug therapy. The scope of possible combinations of a compound ofthe invention and one, two or more active substances are within theknowledge of one skilled in the art for the treatment of anFLAP-mediated disorder.

Specifically, the combination of a FLAP modulator with prostaglandinmodulators, cyclooxygenase-1 modulators, or cyclooxygenase-2 modulatorsmight be used to treat inflammatory and autoimmune diseases and/ordisorders as well as cardiovascular diseases and/or disorders, orvascular injury (Z. Yu et al., “Disruption of the 5-lipoxygenase pathwayattenuates atherogenesis consequent to COX-2 deletion in mice,” Proc.Natl. Acad. Sci. USA, 2012, 109(17), 6727-32; Z. Yu et al., “MyeloidCell 5-Lipoxygenase Activating Protein Modulates the Response toVascular Injury,” Circ. Res., 2012, Epub Dec. 18). Due to the synergy ofhistamine and leukotrienes, the combination of a FLAP modulator and ahistamine receptor 1 or 4 antagonist might have utility in treatingrespiratory, allergic, dermatological and autoimmune disorders (A.Reicin et al., “Montelukast, a leukotriene receptor antagonist, incombination with loratadine, a histamine receptor antagonist, in thetreatment of chronic asthma,” Arch. Intern. Med., 2000, 160(16),2418-88; S. Sanada et al., “The effectiveness of montelukast for thetreatment of anti-histamine-resistant chronic urticaria,” Arch.Dermatol. Res., 2005, 297(3), 134-38).

Formulations

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

The compounds of the present invention may be formulated into variouspharmaceutical forms for administration purposes. Methods of formulatingpharmaceutical compositions have been described in numerous publicationssuch as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revisedand Expanded, Volumes 1-3, edited by Lieberman et al; PharmaceuticalDosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al;and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, editedby Lieberman et al; published by Marcel Dekker, Inc.

F) Biological Examples

The ability of the compounds of the present invention to treat aFLAP-mediated disease and/or disorder, or associated symptoms orcomplications thereof, was determined using the following procedures.Binding assay data represent the average value obtained from twodifferent assay plates, with samples run in duplicate on each plate.Human whole blood assay data represent a single replicate on an assayplate using whole blood from at least one healthy donor.

FLAP Binding Assay

The assay below is used to test the modulatory activity of compoundsagainst FLAP. Human and mouse FLAP-encoding DNA was amplified bypolymerase chain reaction and cloned into pFastBac1 (Invitrogen) with aNH2-terminal 6-His tag for expression in Spodoptera frugiperda (Sf-9)cells. FLAP-containing membranes were prepared as was a FITC-labeledFLAP modulator(3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropanoicacid). The FLAP binding assay is performed in HTRF format (homogeneoustime resolved fluorescence). FLAP-containing membranes (1 μg/well finalfor human) are incubated in the presence of the HTRF ligand,[5-[({[2-(2-{3-[3-(tert-butylsulfanyl)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropanoyl}hydrazino)-2-oxoethyl]sulfanyl}acetyl)amino]-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoicacid] (25 nM final), a terbium labeled anti-His tag antibody (0.5ng/well final, from Cisbio) and compounds. The reaction is allowed toproceed for two hours after which the plate is read on an Envision platereader in HTRF mode. Data are expressed as a HTRF ratio.

For human FLAP binding assays, data are analyzed with 3DX Explorersoftware. A ratio is calculated with the relative light units at 520 nmover the relative light units at 495 nm. For analysis, data frommultiple runs are averaged and each compound may be tested in 2 to 20runs. Each run comprises two plates and each plate includes duplicates.Data from each plate is averaged and data are imported into 3DX. Thedata from multiple runs are aggregated as the average of duplicates ofthe calculated ratios in order to calculate K_(i) and IC₅₀ values. Theletters ND and/or the absence of data in any of the boxes in Table 5 andTable 6 indicates that K_(i) or IC₅₀ values were not determined.

Human Whole Blood Assay

An in vitro cellular assay was performed using human whole bloodcollected in heparin-containing tubes, which was used to test theability of compounds to modulate the leukotriene pathway in human wholeblood. The blood was diluted 1:1 in RPMI medium, pre-incubated for 15min at 37° Celsius with test compounds at various concentrations, andthen stimulated with calcium ionophore, A23187 (7 μg/mL), for 30 min at37° Celsius. The samples were then centrifuged and plasma was removed.The plasma was diluted in assay buffer and LTB₄ levels were measuredusing a commercial kit (Enzo Life Sciences). The concentration of eachcompound that was required for half-maximal inhibition (modulation) ofrecombinant enzyme activity (IC₅₀) was calculated by a 4-parameterequation using the program GraphPad Prism (GraphPad software).

TABLE 5 FLAP binding and Human Whole Blood assay data FLAP Binding wildtype HTRF Human Whole Blood Cmp No. K_(i) (μM) LTB4 IC₅₀ 1:1 (μM) A0.064 0.5311 B 0.354 0.9601 1 0.286 0.5882 2 0.158 0.5255 3 0.250 0.27124 0.004 0.2983 5 0.011 0.2632 6 0.014 1.2165 7 0.007 1.4025 8 0.750 90.808 10 0.866 11 0.750 12 0.090 13 0.250 1.2900 14 0.122 2.2888 150.193 1.2379 16 0.098 0.4670 17 0.016 0.2755 18 0.120 1.1684 19 0.1000.8115 20 0.005 >10 21 0.008 4.1267 22 0.006 >10 23 0.002 0.3633 240.100 >10 25 0.012 0.5758 26 0.020 >10 27 0.006 0.8048 28 0.304 29 0.2241.0605 30 0.354 31 0.170 1.9552 32 0.354 33 0.250 1.4135 34 0.304 1.569635 0.173 1.1387 36 0.220 2.5433 37 0.250 2.4963 38 0.250 0.7364 39 0.75040 0.612 41 0.250 1.3462 42 2.000 43 0.430 44 1.500 45 0.193 0.7196 460.008 5.6157 47 0.042 0.2998 48 0.012 0.1751 49 0.132 1.1471 50 1.500 510.324 52 0.366 0.6797 53 0.138 0.6449 54 0.296 0.9087 55 0.152 0.5550 560.082 0.6437 57 0.036 0.3454 58 0.030 0.3736 59 0.327 1.5371 60 0.1160.7318 61 0.262 0.6971 62 0.315 0.8316 63 0.120 0.2125 64 0.086 0.275365 0.018 0.1067 66 0.422 0.7534 67 0.176 0.7268 68 0.750 69 0.030 0.073970 0.034 0.4127 71 0.620 72 0.018 0.7372 73 0.275 1.0249 74 0.750 750.370 76 0.250 1.7656 77 0.200 1.3823 78 0.173 1.2888 79 0.250 2.2295 800.304 3.2931 81 0.394 82 0.304 83 0.037 0.6046 84 0.070 0.8865 85 0.02810 86 0.005 0.0351 87 0.001 0.0067 88 0.004 0.0361 89 0.004 0.0222 900.0538 91 0.001 0.0048 92 6.6635 93 0.003 0.0308 94 0.027 0.1010 950.005 >1 96 0.007 0.0338 97 0.032 0.1534 98 0.008 0.1751 99 0.006 0.0407100 0.001 0.0126 101 0.023 0.9143 102 0.002 0.1028 103 0.035 0.6750 1040.100 2.8054 105 0.250 106 0.084 0.3759 107 0.0069 0.1770 108 0.02461.3056 109 0.0089 0.3075 110 0.0024 0.0522 111 0.0019 0.0654 112 0.01480.1812 113 0.0270 0.6076 114 0.0172 0.3746 115 0.297 1.1064 116 0.01460.5034 117 2.500 118 0.0105 0.0657 119 0.006 0.0263 120 0.304 121 0.250122 0.004 0.4596 123 0.007 4.4771 124 0.003 0.1192 125 0.250 126 0.01070.4059 127 2.200 128 0.297 129 0.119 0.2813 130 0.0037 0.0841 131 0.00560.0679 132 0.0170 0.1327 133 0.0102 0.0796 134 0.0062 0.0397 135 0.00130.0124 136 0.0035 0.0459 137 0.0037 0.0510 138 0.0055 0.0703 139 0.00390.0485 140 0.0013 0.0117 141 0.0050 0.0586 142 0.0017 0.0185 143 0.00290.0377 144 0.0011 0.0223 145 0.0054 0.1774 146 0.0004 0.0045 147 0.00640.1854 148 0.1007 149 0.0013 0.1119 150 0.1764 3.5859 151 0.0089 0.0754152 0.0625 >10 153 0.0023 0.4245 154 0.0125 >10 155 0.0041 0.1701 1562.236 157 0.0206 0.1090 158 0.0078 0.0359 159 0.0557 3.3052 E 0.09951.0950 160 0.0947 0.4935 161 0.0222 0.0880 162 0.0072 0.1238 163 0.07040.4941 164 0.0368 0.1185 165 0.0056 0.3039 166 0.0117 0.1286 167 0.01470.0456 168 0.0028 0.0361 169 0.2053 0.2680 170 0.0903 1.4256 171 0.03980.2519 172 0.394 1.6615 173 0.682 174 0.0054 1.2142 175 0.1 1.2835 F0.075 1.2960 176 0.1 0.8917 177 0.093 0.7711 178 0.354 179 0.750 1800.370 181 0.041 10.0000 182 1.936 183 0.328 >10 184 0.0140 0.8310 1850.0196 1.0074 186 0.0205 0.5309 187 0.0120 0.3551 188 0.0086 1.1036 1890.0098 1.1397 190 0.0472 1.0575 191 0.2500 3.4316 192 0.0053 0.4184 1930.0037 0.7688 194 0.0029 0.1682 195 0.0022 0.4457 196 0.0041 0.8712 1970.750 198 0.0187 2.3681 199 0.0242 1.0566 G 0.0779 0.5748 200 0.15511.3583 201 0.0085 0.0518 202 0.0061 0.0805 203 0.0069 0.0308 204 0.08150.1713 205 0.0402 0.1496 H 0.0723 0.2866 206 0.7690 207 0.0474 0.0726208 0.0465 0.2146 209 0.0233 0.0511 210 2.500 211 0.527 212 0.06401.0950 213 0.0921 1.0146 214 0.0308 1.0872 215 0.620 216 0.866 217 1.250218 0.0773 >5.000 219 >10 220 0.0218 1.117 221 0.5932 222 0.1798 3.475223 >10 224 0.0232 0.2867 225 0.0025 0.0684 226 0.0014 0.0901 227 0.00850.3317 228 0.0244 0.4804 229 0.0077 0.4075 230 0.0025 0.2379 231 2.1389232 1.5907 233 1.6792 234 1.3002 >10 235 0.0033 0.1132 236 0.0022 0.0371237 0.0033 0.0847 238 0.1551 0.5710 239 0.0083 0.1967 240 0.0236 0.1045241 0.0012 0.0207 242 0.0036 0.0300 I 0.090 1.6688 243 0.2355 0.8588 2440.4622 1.8168 245 0.0622 2.8016 246 0.0986 1.5929 247 0.2594 0.4173 2480.2610 10 249 0.2076 1.2636 250 0.0992 0.3567 251 1.1951 252 0.0296 >1253 0.8541 254 0.9922 255 1.1392 1.1387 256 0.4335 0.7180 257 0.03110.3324 258 0.0038 0.0101 259 0.0070 0.1344 260 0.0199 0.1973 261 0.00130.0401 262 0.0196 0.1596 263 0.1375 1.9579 264 >10 265 >10 266 >10267 >10 268 >10 269 0.0009 0.0151 270 0.7995 271 0.0051 0.0853 2720.0005 0.0419 273 >10 274 0.0196 0.1596 275 0.1375 1.9579 276 0.03920.4063 277 0.0177 0.1346 278 0.1000 0.2160 279 0.0675 0.1466 280 >10 2810.1006 0.3696 282 0.0294 >10 283 0.0976 284 >10 285 >10 286 287 2880.3646 289 0.2292 0.7825 290 0.0399 0.5059 291 0.0466 0.5761 292 0.03720.4125 293 0.0165 1 294 0.6914 295 0.0042 0.1488 296 0.0068 0.3499 2970.0144 0.2626 298 >10 299 >10 300 >10 301 >10 302 >10 303 >10 304 >10305 >10 306 >10 307 >10 308 >10 309 >10 310 >10 311 0.0081 0.1099 3120.9745 313 0.0024 0.0270 314 >10 315 1.3649 316 0.2893 317 0.1978 0.4639318 0.0581 0.1031 319 0.3367 0.2845 320 0.0364 0.1674 321 0.1165 >10 3220.5730 323 0.2106 0.1406 324 0.0738 0.2.600 325 0.0095 0.0527 326 0.3584327 0.5278 328 0.1127 0.3125 329 0.0097 0.0390 330 0.0051 >1 331 0.00370.0129 332 0.0458 0.4500

The following compounds were tested in additional runs for the assaysdescribed above and the data is provided in Table 6.

TABLE 6 FLAP binding and Human Whole Blood assay data FLAP binding wildtype HTRF Human Whole Blood Cmp No. K_(i)(μM) LTB4 IC₅₀ 1:1 (uM) A0.0526 0.5311 B 0.0839 0.9601 1 0.0628 0.5882 2 0.0861 0.8954 3 0.11840.2712 4 0.0058 0.2983 5 0.0102 0.2632 6 0.0136 1.2165 7 0.0074 1.4025 8~0.7500 9 ~0.8077 10 ~0.8659 11 ~0.7500 12 ~0.0899 13 0.0271 1.2900 140.0226 2.2888 15 ~0.1933 1.2379 16 0.0199 0.4670 17 0.0125 0.2820 180.0590 1.1684 19 0.0038 0.8115 20 0.0051 >10 21 0.0081 4.1267 220.0059 >10 23 0.0037 0.3633 24 0.0162 >10 25 0.0122 0.5758 26~0.0199 >10 27 0.0064 0.8048 28 0.0662 29 0.0246 1.0605 30 0.0335 31~0.1699 1.9552 32 ~0.3535 33 ~0.2499 1.4135 34 ~0.3041 1.5696 35 ~0.17321.1387 36 ~0.2199 2.5433 37 ~0.2499 2.4963 38 ~0.2499 0.7364 39 ~0.750040 ~0.6123 41 ~0.2499 1.3462 42 ~1.9998 43 ~0.4301 44 ~1.5000 45 ~0.19330.7196 46 0.0069 5.6157 47 0.0418 0.2998 48 0.0121 0.1751 49 ~0.13191.1471 50 0.7872 51 0.3240 52 0.3661 0.6797 53 0.1381 0.6449 54 0.29570.9087 55 0.1516 0.5550 56 0.0819 0.6437 57 0.0356 0.3454 58 0.03030.3736 59 0.3269 1.5371 60 0.1161 0.7318 61 0.2618 0.6971 62 0.31450.8316 63 0.1202 0.2125 64 0.0860 0.2753 65 0.0182 0.1067 66 0.42160.7534 67 0.1762 0.7268 68 0.1355 69 0.0140 0.0739 70 0.0342 0.4127 710.4208 72 0.0237 0.7372 73 0.2748 1.0249 74 0.1747 75 ~0.3699 76 ~0.24991.7656 77 ~0.1999 1.3823 78 ~0.1732 1.2888 79 ~0.2499 2.2295 80 ~0.30413.2931 81 ~0.3937 82 0.2085 83 0.0445 0.6046 84 ~0.0700 0.8865 85 0.0281~10 86 0.0062 0.0351 87 0.0021 0.0067 88 0.0035 0.0361 89 0.0053 0.022290 0.0538 91 0.0008 0.0048 92 6.6635 93 0.0052 0.0308 94 0.0445 0.101095 0.0047 >1 96 0.0071 0.0338 97 0.0317 0.1261 98 0.0084 0.1239 990.0055 0.0407 100 0.0012 0.0126 101 0.0233 0.9143 102 0.0018 0.1028 103~0.0353 0.6750 104 0.0183 2.8054 105 0.0394 106 0.0123 0.3759 107 0.00540.1770 108 0.0281 1.3056 109 0.0112 0.3075 110 0.0026 0.0522 111 0.00240.0654 112 0.0136 0.1812 113 0.0308 0.6076 114 0.0102 0.3746 115 0.05371.1064 116 0.0139 0.5034 117 ~2.4997 118 0.0105 0.0657 119 0.0066 0.0274120 ~0.3041 121 0.0072 122 0.0037 0.4596 123 0.0070 4.4771 124 0.00280.1192 125 ~0.2499 126 0.0107 0.4059 127 ~2.2003 128 ~0.2973 129 ~0.11920.2813 130 0.0037 0.0214 131 0.0056 0.0679 132 0.0170 0.1327 133 0.01020.0796 134 0.0046 0.0397 135 0.0013 0.0124 136 0.0039 0.0566 137 0.00430.0510 138 0.0053 0.0703 139 0.0038 0.0485 140 0.0013 0.0117 141 0.00550.0586 142 0.0017 0.0185 143 0.0029 0.0377 144 0.0011 0.0223 145 0.00540.1774 146 0.0004 0.0045 147 0.0064 0.1854 148 0.1007 149 0.0013 0.1119150 0.1764 3.5859 151 0.0089 0.0754 152 0.0625 >10 153 0.0023 0.4245 1540.0176 >10 155 0.0049 0.1279 156 ~2.2361 157 0.0206 0.1090 158 0.00780.0359 159 0.0557 3.3052 E 0.0995 1.0950 160 0.0947 0.4935 161 0.02220.0880 162 0.0072 0.1238 163 0.0704 0.4941 164 0.0368 0.1185 165 0.00560.3039 166 0.0117 0.1286 167 0.0147 0.0456 168 0.0028 0.0361 169 0.20530.2680 170 0.0903 1.4256 171 0.0398 0.2519 172 ~0.3937 1.6615 173~0.6818 174 0.0039 1.2142 175 ~0.1 1.2835 176 ~0.0750 1.2960 177 ~0.10.8917 178 ~0.0930 0.7711 179 ~0.3535 F ~0.7500 180 ~0.3699 181 0.040710.0000 182 ~1.9364 183 ~0.3279 >10 184 0.0140 0.8310 185 0.0196 1.0074186 0.0205 0.5309 187 0.0120 0.3551 188 0.0086 1.1036 189 0.0098 1.1397190 0.0472 1.0575 191 ~0.2499 3.4316 192 0.0053 0.4184 193 0.0037 0.7688194 0.0029 0.1682 195 0.0022 0.4457 196 0.0041 0.8712 197 ~0.7500 1980.0187 2.3681 199 0.0242 1.0566 G 0.0779 0.5748 200 0.1551 1.3583 2010.0085 0.0518 202 0.0061 0.0805 203 0.0069 0.0308 204 0.0815 0.1713 2050.0402 0.1496 H 0.0723 0.2866 206 0.7690 207 0.0515 0.0780 208 0.04650.1605 209 0.0233 0.0511 210 ~2.4997 211 ~0.5267 212 0.0640 1.0950 2130.0921 1.0146 214 0.0308 1.0872 215 0.7049 216 0.7135 217 1.0378 2180.0773 >5.00034 219 >10 220 0.0218 1.1169 221 0.5932 222 0.1798 3.4754223 >10 224 0.0232 0.2867 225 0.0232 0.2867 226 0.0014 0.0901 227 0.00850.3317 228 0.0244 0.4804 229 0.0077 0.4075 230 0.0025 0.2379 231 2.1389232 1.5907 233 1.6792 234 1.3002 >10 235 0.0033 0.1132 236 0.0022 0.0371237 0.0033 0.0847 238 0.1551 0.5710 239 0.0083 0.1967 240 0.0236 0.1045241 0.0012 0.0207 242 0.0036 0.0300 I ~0.0899 1.6688 243 0.2355 0.8588244 0.4622 1.8168 245 0.0622 2.8016 246 0.0986 1.5929 247 0.2594 0.4173248 0.2610 ~10 249 0.2817 1.2636 250 0.0992 0.3567 251 1.1951 2520.0296 >1 253 0.8541 254 0.9922 255 1.1392 1.1387 256 0.4335 0.7180 2570.0311 0.3324 258 0.0038 0.0101 259 0.0070 0.1344 260 0.0199 0.1973 2610.0022 0.0401 262 0.0196 0.1568 263 0.1375 1.9579 264 0.1013 265 >10266 >10 267 >10 268 >10 269 0.0009 0.0151 270 0.7995 271 0.0051 0.0853272 0.0005 0.0419 273 >10 274 0.0196 0.1568 275 0.1375 1.9579 276 0.03921.8557 277 0.0177 0.1909 278 0.1001 0.2160 279 0.0676 0.1141 280 >10 2810.1006 0.4533 282 0.0294 >10 283 0.0976 0.5378 284 >10 285 >10 2860.0817 1.1882 287 0.0176 >1 288 0.3646 289 0.2292 0.7825 290 0.03990.5059 291 0.0466 0.5761 292 0.0372 0.4125 293 0.0165 0.1004 294 0.6914295 0.0042 0.1881 296 0.0068 0.2829 297 0.0144 0.2125 298 0.8680 2991.9566 300 >10 301 >10 302 >10 303 >10 304 >10 305 >10 306 >10 307 >10308 >10 309 >10 310 >10 311 0.0081 0.2658 312 0.9745 313 0.0024 0.0270314 >10 315 1.3649 316 1.3649 317 0.1979 0.4640 318 0.0582 0.1041 3190.3367 0.2846 320 0.0365 0.1674 321 0.1165 >10 322 0.5731 323 0.21070.1407 324 0.0738 0.2601 325 0.0096 0.0528 326 0.3584 327 0.5278 3280.1128 0.3125 329 0.0097 0.0391 330 0.0051 >1 331 0.0037 0.0129 3320.0459 0.4501 333 0.4211 334 0.0046 0.0527 335 0.0036 0.0369 336 0.00390.0238 337 0.0148 0.1615 338 0.0017 0.0959 339 0.1077 1.6376 340 0.6501341 0.0226 0.1238 342 0.0081 0.0263 343 0.0054 0.0144 344 0.0269 0.0915345 0.0142 0.0151 346 0.0453 0.1762 347 0.0476 0.3961 348 0.0131 0.1467349 0.0310 >1 350 0.0529 0.4491 351 0.0544 0.1242

Throughout this application, various publications are cited. Thedisclosure of these publications is hereby incorporated by referenceinto this application to describe more fully the state of the art towhich this invention pertains.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

The invention claimed is:
 1. A compound of Formula (I)

wherein L is selected from: a bond, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂NH—, —CH₂C(═_(O))NH—; —CH₂C(OH)(H)CH₂—, and —CH₂C(OH)(H)CH₂NH—;R₁ is selected from: halo, C₁₋₅alkyl, C₃₋₆cycloalkyl, andcyclohexylmethyl; R₂ is selected from: H, C₁₋₄alkyl, hydroxyl, amino,cyano, —CH₂C(═O)O—(tert-butyl), —CH₂C(═O)O-(ethyl), —CH₂C(═O)OH,—NHS(═O)₂CH₃, tert-butyl (dimethyl)silyl-oxy, —NHCH₃, —N(CH₃)₂,—NH-(isopropyl), optionally substituted phenyl, optionally substituted5-membered or 6-membered heteroaryl, C₃₋₆cycloalkyl, and optionallysubstituted heterocyclyl; wherein the 5-membered or 6-memberedheteroaryl, the heterocyclyl, or the phenyl is optionally andindependently substituted with 1-4 substituents selected from the groupconsisting of: C₁₋₄alkyl, —CH₂-methoxy, —C(═O)OH, —CH₂C(═O)OH,—C(═O)—O—CH₂CH₃, —C(═O)—O—CH₃, —C(═O)—O-(tert-butyl), —NH₂, —N(CH₃)₂,—NH-(isobutyl), —NH(CH₂)₂NHC(═O)—O-tent-butyl, —NH(CH₂)₂NH₂,—NH(CH₂)₂N(CH₃)_(2,) —C(═O)NH_(2,)—C(═O)CH₃, oxo, halo, hydroxyl,methoxy, trifluoromethyl, trifluoromethoxy, methoxymethyl, —S(═O)₂CH₃,—S(═O)₂NH₂, —S(═O)₂NH(CH₃), —S(═O)₂N(CH₃)₂, —S—CH₃, cyano,1H-tetrazol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl,4′-(trifluoromethyl) phenyl, benzyl, 1,5-dioxa-9-azaspiro[5.5]undecan-9-yl, 5-pyrimidine-2-amine, andpentafluoro-lambda˜6˜-sulfanyl; ring A is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1,wherein the compound isselected from the group consisting of:6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine,7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenol,7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile,7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfonyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzonitrile,7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,3-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide,4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzamide,7-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,(4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)aceticacid,4-{[6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy]methyl}benzoicacid,3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine,5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine,6-Cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol,6-Cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol,6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol,7(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,2(6-Cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine,7(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine,5(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrim idin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-b]pyridine,5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine,2-[6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenoxy]pyrimidin-4-amine,and5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine,and and their pharmaceutically acceptable salts thereof.
 3. Apharmaceutical composition comprising at least one compound of claim 1and at least one pharmaceutically acceptable carrier.
 4. Thepharmaceutical composition of claim 3 comprising at least one compoundof claim
 2. 5. A process for making a pharmaceutical compositioncomprising admixing any of the compounds according to claim 1 and apharmaceutically acceptable carrier.